AU610629B2 - Improvements in or relating to leukotriene antagonists - Google Patents
Improvements in or relating to leukotriene antagonists Download PDFInfo
- Publication number
- AU610629B2 AU610629B2 AU20966/88A AU2096688A AU610629B2 AU 610629 B2 AU610629 B2 AU 610629B2 AU 20966/88 A AU20966/88 A AU 20966/88A AU 2096688 A AU2096688 A AU 2096688A AU 610629 B2 AU610629 B2 AU 610629B2
- Authority
- AU
- Australia
- Prior art keywords
- formula
- group
- phenyl
- alkyl
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 239000003199 leukotriene receptor blocking agent Substances 0.000 title description 4
- -1 2H-tetrazolyl ring Chemical group 0.000 claims abstract description 86
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 65
- 238000000034 method Methods 0.000 claims abstract description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 35
- 150000002617 leukotrienes Chemical class 0.000 claims abstract description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 21
- 125000005843 halogen group Chemical group 0.000 claims abstract description 21
- 125000001246 bromo group Chemical group Br* 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 8
- 125000001033 ether group Chemical group 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 4
- 229910003827 NRaRb Inorganic materials 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 68
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 52
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 18
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 150000003536 tetrazoles Chemical class 0.000 abstract description 38
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 abstract description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 162
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 87
- 239000000203 mixture Substances 0.000 description 79
- 239000000243 solution Substances 0.000 description 75
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 238000006243 chemical reaction Methods 0.000 description 53
- 239000000047 product Substances 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 50
- 238000004458 analytical method Methods 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
- 239000000543 intermediate Substances 0.000 description 34
- 239000003921 oil Substances 0.000 description 34
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 239000003153 chemical reaction reagent Substances 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- 101150041968 CDC13 gene Proteins 0.000 description 21
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 21
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 20
- 239000002243 precursor Substances 0.000 description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 16
- 239000002244 precipitate Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 159000000000 sodium salts Chemical group 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 125000005647 linker group Chemical group 0.000 description 11
- JKVRTUCVPZTEQZ-UHFFFAOYSA-N tributyltin azide Chemical compound CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-] JKVRTUCVPZTEQZ-UHFFFAOYSA-N 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000012467 final product Substances 0.000 description 10
- 125000003831 tetrazolyl group Chemical group 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 230000002378 acidificating effect Effects 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 229920002472 Starch Polymers 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 8
- 239000000377 silicon dioxide Substances 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- 235000019698 starch Nutrition 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 235000008504 concentrate Nutrition 0.000 description 6
- JSYGRUBHOCKMGQ-UHFFFAOYSA-N dichloramine Chemical compound ClNCl JSYGRUBHOCKMGQ-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000012038 nucleophile Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 210000003405 ileum Anatomy 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012039 electrophile Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000011369 resultant mixture Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 4
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 4
- 238000010626 work up procedure Methods 0.000 description 4
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 3
- QBISYTPYWPBCFW-UHFFFAOYSA-N 1-[2-hydroxy-3-propyl-4-[[4-(2h-tetrazol-5-ylmethyl)phenoxy]methyl]phenyl]ethanone;sodium Chemical compound [Na].C1=CC(C(C)=O)=C(O)C(CCC)=C1COC(C=C1)=CC=C1CC1=NNN=N1 QBISYTPYWPBCFW-UHFFFAOYSA-N 0.000 description 3
- CQPGDDAKTTWVDD-UHFFFAOYSA-N 4-bromobutanenitrile Chemical compound BrCCCC#N CQPGDDAKTTWVDD-UHFFFAOYSA-N 0.000 description 3
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- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000001263 acyl chlorides Chemical class 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 3
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
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- 239000002024 ethyl acetate extract Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- ZIPLUEXSCPLCEI-UHFFFAOYSA-N iminomethylideneazanide Chemical compound [NH-]C#N ZIPLUEXSCPLCEI-UHFFFAOYSA-N 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- 150000004965 peroxy acids Chemical class 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 2
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 2
- ZNQLTPORMBBLIB-UHFFFAOYSA-N 1-[2-hydroxy-4-[[4-[[2-(3-methylsulfanylpropyl)tetrazol-5-yl]methyl]phenoxy]methyl]-3-propylphenyl]ethanone Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1COC(C=C1)=CC=C1CC1=NN(CCCSC)N=N1 ZNQLTPORMBBLIB-UHFFFAOYSA-N 0.000 description 2
- RYBIEXQYFAIFLK-UHFFFAOYSA-N 1-[4-[[4-[[2-(5-bromopentyl)tetrazol-5-yl]methyl]phenoxy]methyl]-2-hydroxy-3-propylphenyl]ethanone Chemical compound C1=CC(C(C)=O)=C(O)C(CCC)=C1COC(C=C1)=CC=C1CC1=NN(CCCCCBr)N=N1 RYBIEXQYFAIFLK-UHFFFAOYSA-N 0.000 description 2
- ITXLVCGXRFUPGI-UHFFFAOYSA-N 1-[4-[[4-[[2-(6-bromohexyl)tetrazol-5-yl]methyl]phenoxy]methyl]-3-ethyl-2-hydroxyphenyl]ethanone Chemical compound C1=CC(C(C)=O)=C(O)C(CC)=C1COC(C=C1)=CC=C1CC1=NN(CCCCCCBr)N=N1 ITXLVCGXRFUPGI-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
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- 201000003883 Cystic fibrosis Diseases 0.000 description 2
- 102220501443 Cytosolic iron-sulfur assembly component 3_C27N_mutation Human genes 0.000 description 2
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical class CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
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- 230000000763 evoking effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 102000003835 leukotriene receptors Human genes 0.000 description 1
- 108090000146 leukotriene receptors Proteins 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- YSVZADAAWQNYCF-UHFFFAOYSA-N methylsulfanylmethane;sodium Chemical compound [Na].CSC YSVZADAAWQNYCF-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000063 preceeding effect Effects 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 229960005078 sorbitan sesquioleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000012058 sterile packaged powder Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The instant invention provides disubstituted tetrazoles that antagonizes the effect of leukotrienes C4, D4 and E4 in selected tissues. The disubstituted tetrazoles are used in pharmaceutical formulations and methods of treatment of conditions caused by excessive amounts of leukotrienes C4, D4 or E4 or any combination thereof, and have the formula: <CHEM> wherein: R1 is C1 to C3 alkyl; R2 is C1 to C6 alkyl or C3 to C6 alkenyl; R3 is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NRaRb wherein Ra and Rb are the same or different and are a hydrogen atom, C1 to C4 alkyl, phenyl, benzyl, or C1 to C4 acyl; R4 and R5 are the same or different and are a hydrogen atom or C1 to C3 alkyl; W is from one to six; Z is O, S or a group of the formula -NRe , (wherein Re is a hydrogen atom, C1 to C4 alkyl, C1 to C4 acyl, phenyl, or benzyl); n is 0 to 6; Rc and Rd are the same or different and are hydrogen, hydroxy, halo or an ether group of the formula -O-(C1 to C6 alkyl); [Tet] is a disubstituted 1H- or 2H-tetrazolyl ring of the formula <CHEM> wherein: L is 1) C1 to C10 alkylidene; or 2) a group of the formula <CHEM> wherein y is 1 to 3 (and the phenyl ring is bonded to A); A is 1) 5-(tetrazolyl); 2) carboxy; 3) -NRfRg,wherein Rf and Rg are the same or different and are a hydrogen atom, C1 to C4 alkyl, phenyl, benzyl or C1 to C4 acyl; or 4) a group of the formula <CHEM> wherein q is 0, 1 or 2 and Rh is C1 to C4 alkyl, phenyl or benzyl; or a pharmaceutically-acceptable salt thereof.
Description
0Y1 29 S F Ref: 64168 FORM COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE: Class Int Class Complete Specification Lodged: Accepted: a Published: Priority: .c t Relatu Art: Name and Address of Applicant: Eli Lilly and Company Lilly Corporate Center Indianapolis Indiana 46285 UNITED STATES OF AMERICA Address for Service: Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia Complete Specification for the invention entitled: Improvements in or Relating to Leukotriene Antagonists The following statement is a full description this invention, including the best method of performing it known to me/us 5845/3 016.- I I i i i I_ X-7387 -1- IMPROVEMENTS IN OR RELATING TO LEUKOTRIENE ANTAGONISTS This invention relates to novel chemical agents which are selective leukotriene antagonists that can be used therapeutically in the treatment of allergic disorders such as asthma.
Research in the area of allergic reactions of the lung has provided evidence that arachidonic acid derivatives formed by the action of lipoxygenases are related to various disease states. Some of these arachidonic acid metabolites have been classified as members of a family of eicosatetraenoic acids termed leukotrienes. Three of these substances are currently thought to be major components of what has been previously called slow reacting substance of anaphylaxis
(SRS-A).
Over the past decade, the association of leukotrienes to a variety of clinical conditions has been appreciated. Evidence obtained over the past few years has shown the presence of leukotrienes in sputum of patients with chronic bronchitis (Turnbull, et al., Lancet II, 526 (1977)) and cystic fibrosis (Cromwell, et al., Lancet II, 164 (1981)), suggesting a role of leukotrienes in the pathology of those diseases.
Furthermore, Lewis and colleagues [Int. J. Immunopharmacology, 4, 85 (1982)] have recently detected material in rheumatoid synovial fluid that reacts antigenically with antibody to LTD 4 This may hallmark the existence X-7387 -2of leukotriene permeability factors that, together with
LTB
4 augment the inflammatory process in the diseased joints.
In an attempt to treat the various conditions which have been associated with excess leukotrienes, a variety of agents have been prepared which are antagonists to leukotrienes receptors. See, U.S. Patent No. 4,661,505.
According to the present invention there are provided compounds of the Formula I /R R
R
N 4 d -(CH2)'n---Tet] R*i s I wherein: RI is C 1 to C 3 alkyl;
R
2 is Ci to C 6 alkyl or C 3 to C 6 alkenyl;
R
3 is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NR R b ab wherein R and R are the same or different and are a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl, or Ci to C 4 acyl;
R
4 and Rs are the same or different and are a hydrogen atom or Ci to C 3 alkyl; W is from one to six; X-7387 -3- Z is O, S or a group of the formula
-NR
e (wherein Re is a hydrogen atom, Ci to C 4 alkyl, CI to C 4 acyl, phenyl, or benzyl); n is 0 to 6; R and R are the same or different and are c d hydrogen, hydroxy, halo or an ether group of the formula -0-(CI to C 6 alkyl); [Tet] is a disubstituted 1H- or 2H-tetraz lyl ring of the formula:
N
IN- -L-A
A-L-N
N
or
N
AL-
wherein: N L is 1) C, to C 10 alkylidene; or 2) a group of the formula
-(CH
2 *y.
-i I_ X-7387 -4wherein y is 1 to 3 (and the phenyl ring is bonded to and A is 1) 2) carboxy; 3) -NRfRg, wherein Rf and R are the same or different and are a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl or Ci to C 4 acyl; or 4) a group of the formula (0) h wherein q is 0, 1 or 2 and Rh is C, to C 4 alkyl, phenyl or benzyl; and pharmaceutically-acceptable salts thereof.
The invention also provides for pharmaceutical compositions comprising of a compound of Formula I and a pharmaceutically-acceptable carrier. Also provided are methods of use for treating asthma specifically, and, in general, diseases caused by the release of an excessive amount of leukotrienes C 4
D
4 and E 4 In Formula I, the term "CI to C 6 alkyl" refers to the straight and branched aliphatic radicals of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, sec-isoamyl (1,2-dimethylpropyl), tert-amyl (1,1-dimethylpropyl), hexyl, isohexyl (4-methylpentyl), sec-hexyl (1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
R
X- 7387 1,2, 2-trimethyipropyl, 1,1, 2-trimethyipropyl, and the like. The term "C 1 to C 6 alkyl"' includes within its definition the definition of the terms "C 1 to C 4 alkyl" and "1C, to C 3 alkyl".
The term "CS-Ce alkenyl" refers to straight and branched radicals of three to six carbon atoms such as allyl, isopropenyl, butenyl, isobutenyl, 3-methyl-2butenyl, n-hexenyl, and the like.
The term "IC 1 to C 4 acyl"' includes formyl, acetyl, n-propionyl, iso-propionyl, n-butanoyl, secbutanoyl, iso-butanoyl, and tert-butanoyl. The term "halo" refers to fluoro, chloro, bromo, and iodo.
The term "1 C 1 to CIO alkylidene" refers to straight or branched divalent, hydrocarbon chains such as -CHU 2 CU(C 3 -C(CU 3 2 -F CU(C 2
H
5 -CH 2 CH 2 -CH 2 C(CH 3 -CH(CH 3
)CHU
2 CH(C 3 )CH(CH 3
-CH
2 C(CU 3 2 CH 2 CH(C 2
H
5 -CH 2 CH 2 CH 2 CU(C 3 )CH 2
CH
2 -1 -CH 2 C(C 3 )CH 2
CHU
2 C(C 2
H
5 )CH 2
CH
2 CH 2 C(C 2
H
5 -C(CU 3 2
CH
2
CH
2 CU(C 3 )CH 2 C(C 3
-CHU
2
CHU
2
CHU
2
CH
2 CH2 C(C 3 2
CH
2
CH
2
CHU
2 C(CU 3 2
CH
2
CHU
2
CH
2 C(C 2
UH
5
)CHU
2 -H2 CH2 CH2 CH 2
CU
2 CU(C 3
)CH
2
CH
2 CH2 CH21 -CHU CU CU CU CU CU 2-1 -(CHU 2 7
(CHU
2 8 (CH 2 9
-(CHU
2 1 0 -CH 2 CU(CH 3
)-(CHU
2 )4-1 (CHU 2 2 CU(C 2
UH
5
)-(CHU
2
-CHU
2 CU(C 3
)-(CHU
2 2 CH(C 2
U
5
)-(CHU
2 2 and the like. The term "1C, to C 10 alkylidenell includes the definition of straight chain and branched alkylidene groups of the partial formula -(CU 2 n- (when n is one through 6) that are bonded to the [Tet] group on one end and the phenyl group on the other end in the above Formula I.
X-7387 -6- The pharmaceutically-acceptable salts of this aspect of the invention include salts derived from inorganic bases, such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines, such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkylamines, and the like.
Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine, and the like. The potassium and sodium salt forms are particularly preferred with the sodium salt form being the most preferred.
Those skilled in the art will recognize that, when alkyl or alkylidene groups are branched, various stereoisomers will exist. This invention is not limited to any particular stereoisomer but includes all possible individual isomers and racemates of the compounds of Formula I and Formula II. Similarly, when an alkene group is present, both the individual cis and trans isomers and their mixture are included as part of this invention.
A preferred group of the final product compounds of Formula I is composed of compounds wherein: RI is methyl;
R
2 is n-propyl;
R
3
R
4 Rs, Rc' and R d are a hydrogen atom; Z is O; W is 1; n is 0 or 1; L i I X-7387 -7- [Tet] is a group of the formula:
N
-L-A or A-L-N L 1) CI to C 6 alkylidene; or 2) a group of the formula -(CH2 wherein y is one (and the phenyl ring is also bonded to A); A is 1) 2) a group of the formula -NR R wherein Rf and R are each methyl; 3) a group of the formula (0) wherein
R
h is methyl; or 4) a carboxylic acid; or a pharmaceutically-acceptable base addition salt thereof.
A more preferred group of the above final product compounds are the bis(tetrazole) compounds X-7387 -8wherein the 5-position of the interior tetrazole is bonded to the interior phenyl ring (the ring substituted with R and Rd) through a methylene group; in other words, wherein A is a 5-(tetrazolyl) ring and n is one.
Two preferred groups of the latter bis(tetrazole) compounds are distinguished by the position of the -L-A groups on the interior tetrazolyl ring within the N-2 preferred group is a more preferred group that has L as a methylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, or a 2,2-dimethyl tetramethylene group (bonded through the C-l position to the A group); or when L is a group of the formula a -CH2- (wherein the phenyl group is also bonded to A).
The most preferred compounds in the immediately preceeding more preferred group occurs when L is C 3 in other words, a compound of the Formula III 0 0 N
N
O N and the corresponding 2-H (exterior tetrazole) isomer, and especially the sodium salt therof.
A second more preferred group of above (preferred) final product compounds are the exterior carboxy aD wherein R and R b are the same or different a b and are a hydrogen atom, Ci to C 4 alkyL, phenyl, benzyl, or Ci to C 4 acyl; Jl Ii i SX-7387 -9i compounds, wherein A is carboxy) and the interior i tetrazole is bonded at the 5 position to the interior i phenyl ring by a methylene group n is one). A preferred group of these exterior acid compounds occurs when the exterior linking group L is a straight-chain
C
1
C
3 or C 4 (methylene, trimethylene or tetramethylene) group. A more preferred group occurs when the straight chain C 1
C
3 or C 4 exterior linking group L is bonded at the N-2 position of the interior tetrazole, and espei 10 cially so when the L group bonded at the N-2 position is trimethylene.
A second aspect of the invention is intermediate compounds of the Formula II.
I 15 4 R Rd c R- -Z-0 -(CH2) n--Tet-L-B]
S\R
2
II
i n* wherein: RI is C 1 to C 3 alkyl;
R
2 is CI to C 6 alkyl or C 3 to C 6 alkenyl;
R
3 is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NR R b wherein R and Rb are the same or difa b ferent and are a hydrogen atom, CI to C 4 alkyl, phenyl, benzyl, or C 1 to C 4 acyl;
R
4 and Rs are the same or different and are a hydrogen atom or C 1 to C 3 alkyl; y wherein y is 1 to 3 (and the S ./3 XiiCFI X-7387 W is from one to six; Z is 0, S or a group of the formula -NR e (wherein Re is a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl or Ci to C 4 acyl); n is 0 to 6; R and R are the same or different and are a c d hydrogen atom, hydroxy, halo or an ether group of the formula -O-(Ci to C 6 alkyl); [Tet-L-B] is a disubstituted 1H- or 2Htetrazolyl ring of the formula N L-B
P
L-B
or
N~N
L i a X-7387 -11wherein: L is 1) C 1 to Clo alkylidene; or 2) a group of the formula an 1 jci i c os wherein y is 1 to 3 and the phenyl ring is also bonded to B; and B is 1) cyano; 2) halo; or 3) a group of the formula -COOR 6 wherein R 6 is ethyl or a carboxyprotecting group.
The terms "carboxy-protecting group" and "protected carboxy" as used in the application refer to one of the carboxylic acid substituents commonly employed to block or protect the carboxylic acid functionality while reacting other functional groups on the compound. Examples of such carboxylic acid protecting groups include tert-butyl, 4-methoxybenzyl, benzhydryl (diphenylmethyl), benzyl, para-nitrobenzyl, 2,4,6trimethoxybenzyl, trityl, 4-methoxytrityl, 4,4'dimethoxytrityl, and 4,4',4''-trimethoxytrityl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) (such as alkylation) on other positions of the final products of Formula I and the intermediates of Formula II and can be removed at the appropriate a a 00? 310 n -k,2 =6 X-7387 -12point without disrupting the remainder of the molecule.
Preferred carboxylic acid protecting groups include benzyl, benzhydryl (diphenylmethyl), para-nitrobenzyl and 4-methoxybenzyl, with the more preferred groups being benzhydryl and para-nitrobenzyl. Similar carboxyprotecting groups used in the heterocyclic art are similarly embraced by the above terms. Further examples of these groups are found in E. Haslam in "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, 1973, Chapter 5, and T. W.
Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, 1981, Chapter A preferred group of the intermediate compounds of Formula II occurs when:
R
1 is methyl;
R
2 is n-propyl;
R
3
R
4 Rs, R c and Rd are each hydrogen; Z is 0; W is 1; n is 0 or 1; [Tet-L-B] is a disubstituted 1H- or 2Htetrazolyl ring of the formula: -L or
L-B
L is 1) C 1 to C 6 alkylidene; or L :-i I 71 i; X-7387 -13- 2) a group of the formula -(CH2) wherein y is one (and the phenyl ring is also bonded to and B is cyano, bromo, or ethyl ester.
The most useful groups of intermediates occurs within the above preferred group of intermediates. The first such group has B as cyano, the second has B as the ethyl ester, and the third has B as bromo. All three groups set n equal to 1; thus the 5-position of the interior tetrazolyl ring is bonded through a methylene group to the interior phenyl ring.
The above group of cyano intermediates (B is cyano) contains two further preferred groups. One such group has the interior linking group L as straight chain
C
1 Cs or C 4 alkylidene [methylene, trimethylene or tetramethylene, respectively], which L group is bonded to the N-1 position of the interior tetrazolyl ring.
The other preferred group of cyano intermediates occurs when either L is methylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or 2,2-dimethyltetramethylene, (wherein the C-l position of the tetramethylene group is bonded to or when L is a group of the formula -CH2--* o o 0 00M E 5845/3 i I I-IPRO 1! X-7387 -14- (wherein the phenyl ring is bonded to and L in turn is bonded at the other end to the N-2 position of the interior tetrazolyl group. This latter group of cyano intermediates contains an especially useful compound, wherein L is a straight-chain C 3 alkylidene trimethylene) group.
The above (most useful) group of ethyl ester intermediates B is the ethyl ester) also contains a preferred group of compounds. The preferred group has L as a C 1
C
3 or C 4 straight-chain alkylidene methylene, trimethylene or tetramethylene) group. A more preferred group additionally has one end of such L group bonded to the N-2 position of the interior tetrazolyl ring.
The third of the above most useful groups is the bromo group of intermediates (B is bromo). In the bromo group, compounds wherein L is trimethylene, pentamethylene, or hexamethylene, are preferred, and especially so when one end of these L groups is bonded to the N-2 position of the interior tetrazole ring.
Another preferred group of bromo compounds occurs when L is trimethylene which bonded at one end to the N-l position of the interior tetrazole.
According to another aspect of the invention there is provided a process for preparing the compounds of Formula I.
The final compounds (Formula I) are synthesized from the instant intermediate compounds by methods well known in the art. For example, when B in Formula II is halo, the intermediate can be converted to the cyano intermediate (B cyano) or to the final products wherein 0 i r I~ 'I r I L i X-7387 A is the amine group -NRfRg or the thioether group -S-Rh. Thus, the halo intermediate can be reacted with a source of nucleophilic cyanide anion under SN 2 conditions. Typically, sodium or potassium cyanide (usually in excess) is reacted with the halo intermediate in a polar, aprotic solvent (such as dimethylsulfoxide or N,N-dimethylformamide) at preferably elevated temperatures (50 0 C to the reflux temperature of mixture, although room temperature is also acceptable).
The halo intermediates can be converted to the mercapto final products by reacting the halo intermediate with the corresponding alkyl, phenyl or benzyl mercaptan. The reaction is carried out in a polar aprotic solvent such as dimethylsulfoxide. Heating the reaction mixture is optional. Under similar conditions the "amine" final product (A -NR R can be synthesized from the halo intermediate. The appropriate amine (or amide) HNR R is combined with the halo intermediate (preferably with a large excess of amine) in an aprotic solvent such as acetonitrile at low temperatures.
The mercapto final products synthesized from the halo intermediate can be converted to the corresponding sulfoxide and sulfone (Formula I, q is 1 or 2, respectively) compounds using a mild oxidizing agent.
Sodium periodate is the reagent of choice for the synthesis of the sulfoxide compound. The periodate reagent and the sulfide final product are combined in polar, usually protic solvents (such as a water/methanol mixture) and stirred at room temperature or below.
Peracids are effective reagents for converting the sulfide final product to the sulfone final product. The X-7387 -16sulfide is dissolved in an inert solvent (such as the chlorohydrocarbons, and particularly dichloromethane).
The peracid, such as meta-chloroperbenzoic acid, is added slowly and the mixture stirred at ambient temperature. A slight excess of the peracid is preferably present.
The cyano intermediate of Formula II (B is cyano) can be converted to either the final product (A is 5-(tetrazolyl), as either the 1Hor 2H- isomer or a mixture) or the carboxy final products (or the salts thereof) by methods known in the art. Thus, the cyano intermediates are treated with an alkali metal azide such as sodium azide, ammonium chloride, and (optionally) lithium chloride in a non-reactive highboiling solvent such as N,N-dimethylformamide (DMF), preferably at temperatures from about 60°C to about 125 0 C. Alternatively, tri-(n-butyl)tin azide or tetramethylguanidinium azide, in a solvent such as tetrahydrofuran, dimethoxyethane, diethoxyethane, or the like, may be used in place of the alkali metal azide, ammonium chloride, lithium chloride and DMF.
As indicated above, one method of synthesizing the carboxy final product (Formula I, A carboxy) is to hydrolyze the cyano intermediates. The hydrolysis generally involves heating the cyano derivative in aqueous alcohol in the presence of a base such as sodium or potassium hydroxide. Another method of synthesizing the carboxy final products is to hydrolyze the ester intermediate (Formula II, B is a group of the formula -COOR 6 For example, when Re is ethyl, the ethyl ester intermediate is treated with aqueous sodium or potassium 0 i i rr 1- 11 I X-7387 -17hydroxide solution at a high temperature (such as up to the reflux temperature of the mixture). The free acid final product can be isolated by acidifying (for example, with 5N hydrochloric acid) the (cooled) reaction mixture. If R 6 is a carboxy-protecting group, the group is removed by methods well known in the art.
Thus, the benzhydryl ester can be removed by heating the ester in a strong organic acid such as trifluoroacetic acid or acetic acid. The salts of the carboxy final products are made by reacting the free acid with the appropriate base in the normal manner.
The desired products from the above reactions can be isolated by conventional means, and preferably by chromatography. Column chromatography is a preferred method, and high pressure column chromatography over silica offers a most efficient way of purifying the final products.
I The intermediates of Formula II are made by a variety of methods. For convenience sake the following synthetic discussion will be divided according to the two broad types of substitution pattern of the interior tetrazole. Thus, the first class of reactions ("Class 1 reactions") synthesize intermediates wherein [Tet-L-B] (the interior tetrazole) is bonded to the interior linking group at the 5 position and is of the formula: -L-B or B-L- 0. r .r II I c -Olga"3 X-7387 -18- The second class of reactions ("Class 2") synthesizes intermediates where [Tet-L-B] has the opposite configuration and is of the formula: or B- There are two major Class 1 reactions; one involves alkylating the interior tetrazole when the tetrazole is already a part of the rest of the molecule, the other involves assembling the interior linking group by combining two otherwise complete subunits (one containing the ketophenone and one containing the interior tetrazole ring.
The first Class 1 reaction, called for convenience sake the "core-tetrazole alkylation", is depicted below in Scheme 1: 00004 IL_ I rr I- II r ~1 I b-r L-?ilC~~ 11 L UI X-7387 -19- Scheme 1 Ri R4 R Rd CH-- C 01 \R2 0 X-L-B (alkylating reagent)
II
In the above Scheme, R 1 through Rs, R c Rd' Z, B, L, w and n are as for Formula II. is a good leaving group for S 2 reactions, and is preferably chloro or bromo. (Note that the tetrazole of the starting material can also be 2-H isomer, or alkali metal salt of either the 1H- or 2H-isomer.) The reaction depicted in the above Scheme usually involves approximately equimolar amounts of the starting material and reagent, although other ratios, especially those wherein the alkylating reagent is in excess, are operative. The reaction is best carried out in a polar, aprotic solvent employing an alkali metal salt of the tetrazole starting material, or in the presence of a base, such as an alkali metal hydroxide.
Preferred reaction conditions involve employing the sodium salt of mono-substituted tetrazole in either dimethylformamide or tetrahydrofuran, along with potassium carbonate in a solvent such as acetone or methyl ethyl ketone, or in a mixture of acetonitrile and hexamethylphosphoramide. When the leaving group is X-7387 bromo, a catalytic amount of an iodide salt, such as potassium iodide, may be added to speed the reaction.
The temperature of the reaction is from about ambient temperature to about the reflux temperature of the reaction mixture. When elevated temperatures are employed, the reaction is usually complete in 1-4 hours.
The core tetrazole alkylation depicted in Scheme 1 affords both the N-l and N-2 (interior) tetrazole isomers of the intermediates. These isomers may be separated by standard techniques at any of the intermediate stages or upon formation of the final products.
Such techniques include fractional crystallization or preferably column chromatographic techniques, such as high pressure liquid chromatography.
The second of the two Class 1 reactions is depicted below as Scheme 2: Scheme 2
/R
s j0 R4 -X (Ketophenone Substrate) R1 o- H- R R 6) HZ-o (CH2) L- (Tetrazole Precursor)
II
o a r- X-7387 -21- In the above Scheme, the variables R 1 through
R
5
R
c
R
d w, Z, n, and L are the same as for Formula II. B is either cyano or a group of the formula -COORG.
Finally, X is a good leaving group for SN2 conditions, and is especially a chloro or bromo group.
The reaction depicted in Scheme II above usually employs equimolar amounts of the Ketophenone Substrate and Tetrazole Precursor, although different stoichiometries are completely operative. The reaction is best carried out in nonreactive solvents such as ketones, especially acetone or methyl ethyl ketone, or in dimethylformamide, and in the presence of a base (preferably an alkali metal hydroxide or carbonate, and more preferably potassium carbonate). Especially when X is chloro, a catalyst such as potassium or sodium iodide may be added to increase the reaction rate. Alternatively, ethanol and one equivalent of sodium hydroxide per equivalent of Tetrazole Precursor could be a reaction medium for Scheme 2. The reaction may be carried out at temperatures of about ambient temperature up to the boiling point of the reaction mixture, the former being preferred.
The two major types of Class 2 Reactions the reaction products possess interior tetrazoles bonded to the interior linking group through the N-l or N-2 position) are set forth below as Schemes 3 and 4.
The first such reaction alkylates the interior tetrazole with the rest of the interior linking group (bonded to the ketophenone). This interior tetrazole alkylation is depicted below as Scheme 3:
II~__
X-7387 -22- Scheme 3 /Ro /R3 R
R
-Z
-X
7) Ri HC \2Rz (Linking Group Electrophile)
H
*-L-C0ORe (Tetrazole Nucleophile)
II
In the above Scheme 3 both the N-1 and N-2 isomers of the interior tetrazole are produced. The variable n is one to six, while all other variables used that are a part of Formula II have the same meaning as Formula II. on the Linking Group Electrophile is a good SN 2 leaving group, and is preferably chloro or bromo.
The alkylation of Scheme 3 can employ equimolar amounts of the Linking Group Electrophile and Tetrazole Nucleophile, although the reaction is operative using excesses of either compound. The reaction uses aprotic, 1L X-7387 -23polar solvents, such as ketones (acetone, methylethylketone), and preferably methylethylketone. A weak base (such as sodium or potassium carbonate) is added in at least an equimolar amount of the Tetrazole Nucleophile in order to convert the tetrazole to the anionic form in situ. When the leaving group X is bromo, a catalytic amount of potassium or sodium iodide is preferably added. The reaction is carried out from about 25 0 C to the reflux temperature of the mixture. The reaction is typically complete in two hours. The isomers of the tetrazole product are preferably separated by column chromatography over silica, and more preferably with high pressure liquid chromatography, eluted with a gradient of ethyl acetate in hexane plus 1% acetic acid or methanol in methylene chloride.
The second of the Class II reactions is a three-part sequence of an amine acylation, the dehydration of the resultant amide to the imino chloride, followed by the cyclization of the imino chloride to the tetrazole. This reaction sequence is depicted below as Scheme 4.
*3 aa i X- 7387-2- -24- Scheme 4 l :CH2) n-NH2 (Amine Precursor).
10) Cl L-CN (Acyl Chloride) 11) [core-3-(CH 2 L-CN (Cyano Amide) Dehydration Cl1 12) [core]--(CH 2 )n -HN=e
L-CN
(Imino Chloride) 13) MN3 II) [core----(CH 2 )n N 4 X-7387 In the above Scheme, only intermediates wherein the interior link is bonded to N-l position are produced. All variables used above that are also used in conjunction with the intermediates of Formula II are as defined for Formula II.
The amine acylation reaction above is carried out under standard Schotten-Baumann conditions aqueous alkaline conditions). The reaction uses preferably an approximately equimolar amount of Amine Precursor and Acyl Chloride. (The Acyl Chloride is usually formed immediately before the reaction from the acid by standard methods and used without further purification). The reaction temperature is usually about 0°C.
The reaction is usually complete in about 4 hours. The product is usually isolated by high pressure liquid chromatography over silica gel eluted with toluene/ethyl acetate.
The resultant cyano amide is dehydrated with either thionyl chloride or phosgene in the presense of a sequestering base such as pyridine to give the imino chloride. Again, equimolar amounts of Cyano Amide and SOC1 2 or COC1 2 is usually used. The reaction is preferably carried out in a dry, inert atmosphere. The solvent is generally a highly polar, aprotic one such as an ether (for example, diethyl ether or dimethoxyethane).
The reaction is stirred at 0 C to about room temperature.
The resultant imino chloride is used without further purification.
X-7387 -26- The final reaction in the above scheme uses an alkali metal azide to effect cyclization of the imino chloride to a tetrazole. The reaction conditions for this reaction are those of the conversion of the cyano intermediates of Formula II (B cyano) to the tetrazole final products of Formula I (A Many of the reagents and starting materials in the above Schemes 1 through 4 are known in the art, and some are also commercially available. For example, many of the various precursors, starting materials and reagents are discussed in Marshall et al., U.S. Patent No.
4,661,505, issued April 28, 1987, Goldsworthy et al., U.S. Patent No. 4,595,540, issued June 17, 1986, R. D.
Dillard EPO Patent Application Publication No. 132,366, published January 30, 1985 and EPO Patent Application Publication Nos. 28,063; 110,541; 132,124; and 146,333, all of which are herein incorporated by reference.
o 0 a 4 oane L X-7387 -27- More specifically, the Tetrazole Nucleophile precursor of Scheme 2 above can be synthesized in the manner set forth in Scheme Scheme R R is) (Protected Nucleophilic n Precursor) 16) X-L-B (Alkylating Reagent) 0
-L-B
(Protected Tetrazole Precursor) 6) HZ-* (Tetrazole Precursor) In the above Scheme, Z, R c Rd, n, L and B are as described for Formula II. X is a good leaving group such as chloro or bromo, and P is a hydroxy, mercaptan or amino protecting group, as required.
D
ICGOLP
c C 4 001)~11
I
X-7387 -28- The first reaction in Scheme 5 is an alkylation of the tetrazole, producing a mixture of N-1 and N-2 isomers of the protected Tetrazole Nucleophile. The hydroxy, mercaptan or amino protecting group is then removed to give the required Nucleophilic Tetrazole.
The various protecting groups and the methods for their removal and placement are known in the art and are found in standard works such as T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, 1981.
The larger precursors for the Class II reactions can also be made by methods well known in the art. Both the Reactions of Scheme 3 and Scheme 4 employ a precursor of the following general Formula IV /R R 0 -Z X (CH2) -G Ri n S 20 \R2
IV
wherein all the variables but G are as described in Schemes 3 and 4, and G is chloro, bromo or amino. (The part of the molecule of IV encompassed by brackets will be represented by the symbol ["core"] below in Scheme 6).
The synthesis of the precursor of Formula IV is set forth below in Scheme 6: -41 44 C C 1 L 1 I--
U~PI
X-7387 -29- Scheme 6 R3 0 Ha I o-la t Ri Oi4
'R.
(Ketophenone Substrate) 18) R Rd HZ- (CH 2
OH
n (Hydroxy Tetrazole Precursor) 19) [core--(CH 2 -OH (Hydroxyalkyl core) 7) [coref-(CH 2 -Halo ("Linking Group Electrophile") 9) [core---(CH 2 n-NH ("Amine Precursor") In Scheme 6, the variables in both the Ketophenone Substrate and the Hydroxyalkyl Tetrazole Precursor are as defined for Scheme 2. Furthermore, the Hydroxyalkyl Core is synthesized according to the reaction conditions set forth in Scheme 2. Of course, some undesirable side product will result from alkylation on the "wrong" hydroxy group, the hydroxy of the
-(CH
2 n group. The conversions of the hydroxy group 0 '2 0~ 0 L i -r--l X-7387 to the halo group and of the halo group to the primary amine group are done by methods well known in the art (such as the Gabriel synthesis).
Scheme 7 below sets forth below the synthesis for the Tetrazole Nucleophile of Scheme 3.
Scheme 7 NC-L-B (cyano precursor) tri(n-butyl)tin azide 8) In Scheme 7, L is as defined for Formula II and B is either a group of the formula -COOR 6 or is cyano. The above reaction employes the same conditions as the analogous reaction converting the cyano intermediates of Formula II to the tetrazole final products (A 5-(tetrazolyl) of Formula I. (When B above is also cyano, a large amount of the cyano precursor is used in relation to the tin azide reagent.) According to another aspect of this invention there is provided the use of compounds of Formula I, or a pharmaceutically acceptable salt thereof, in treating a mammal suffering from or susceptible to any condition characterized by an excessive release of leukotrienes.
i t i X-7387 -31- The compounds of Formula I are useful in treating any condition, including clinical conditions, which is characterized by excessive release of leukotrienes C 4
D
4 or E 4 These conditions include immediate type hypersensitivity reactions such as asthma. The compounds described in this invention should also alleviate some of the symptoms of chronic bronchitis and cystic fibrosis and possibly rheumatoid arthritis by virtue of their ability to antagonize leukotrienes. The compounds are also useful for inhibiting the cardiovascular effects of leukotrienes thereby rendering them useful for treating conditions such as shock and ischemic heart disease.
The term "excessive release" of leukotrienes refers to an amount of leukotrienes sufficient to cause the particular condition associated with such amount.
The amount of leukotriene which is considered to be excessive will depend on a variety of factors, including the specific leukotriene(s) involved, the amount of leukotriene required to cause the particular condition, and the species of the mammal involved. As will be appreciated by those skilled in the art, the success of treating a mammal suffering from or susceptible to a condition characterized by an excessive release of leukotrienes with a compound of Formula I will be measured by the regression or prevention of the symptoms of the condition. The compounds of Formula I provide exceptionally high blood levels.
U. U Un e siLI L .r X-7387 -32- Leukotriene antagonism of the claimed final products was demonstrated by the following test procedure: Male, Hartley guinea pigs weighing 200-450 grams were killed by decapitation. A section of terminal ileum was removed, the lumen cleaned, and the tissue divided into 2.5 cm. segments. The ilea were mounted in ml. tissue baths containing Krebs-bicarbonate solution of the following composition in mmoles/liter: KC1, 4.6; CaC1 2 -2H20, 1.2; KH 2
PO
4 1.2; MgSO4-7H20, 1.2; NaC1, 118.2; NaHCO 3 24.8; and dextrose, 10.0. The bath fluid was maintained at 37 0 C. and aerated with 95 percent oxygen and 5 percent CO 2 In addition, the buffer contained 1 x 10+ 6 M atropine to reduce ileal spontaneous activity. Isometric measurements were made with a Grass FT03C force-displacement transducer and recorded on a Grass polygraph as change in grams of force. A passive force of 0.5 g. was applied to the tissues. After an appropriate equilibration period, single submaximal control responses to pure LTD 4 were obtained. Following a five minute exposure of the ileum to an experimental drug, the control concentration of LTD 4 was added to the tissue bath. The response of the ileum to LTD 4 in the presence of the drug was compared to the response in the absence of the drug. Various degrees of LTD 4 antagonism were obtained using 2-4 different concentrations of an experimental compound on a single ileum. The antagonist concentration that produced 50% inhibition of the LTD 4 responses k-log ICs 0 was interpolated from these data using linear regression.
ftan t s L r'- X-7387 -33- For some of the drugs in this series a more detailed analysis of LTD 4 antagonism was made. In these experiments, cumulative concentration-response curves were obtained to LTD 4 in guinea pig ileum and trachea. This was followed by a 30 minute incubation with various concentrations of the experimental drug.
The concentration response curve to LTD 4 was then repeated in the presence of the antagonist. Only one concentration of antagonist was used on a single tissue. K B values were calculated by the method of Furthgott [Ann. N.Y. Acad. Sci., 139, 553 (1967)] using the following equation.
K [Antagonist] B Dose Ratio -1 Dose ratio refers to the concentration of agonist required to elicit 50 percent of the maximal response (EDso) in the presence of the antagonist divided by the ED 50 in the absence of the antagonist.
Calculations were performed with the aid of a computer and a digital plotter. The negative log of the dissociation KB is given for some of the compounds in the table below.
t X-7387 -34- The testing of the compounds of Formula I in procedures is summarized in Table I.
these two Table I Percent inhibition of LTD 4 evoked ileal contractions Example No.
-log ICo 0 pKB 6.65 6.01 6.45 7.76 7.93 7.85 8.42 7.72 8.09 7.55 7.24 7.70 7.26 7.93 7.38 7.70 7.64 7.63 6.37 7.90 6.50 6.37 r i i i X-7387 According to one further aspect of this invention there is provided a pharmaceutical formulation comprising a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, in association with one or more pharmaceutically acceptable carriers or diluents therefor.
The compounds or formulations of the present invention may be administered by the oral and rectal routes, topically, parenterally, for example, by injection and by continuous or discontinuous intra-arterial infusion, in the form of, for example, tablets, lozenges, sublingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base, soft and hard gelatin capsules, suppositories, injectable solutions and suspensions in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injectable solutions.
Advantageously for this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing fror about 5 to 500 mg. (from about 5 to mg. in the case of parenteral or inhalation administration, and from about 25 to 500 mg. in the case of oral or rectal administration) of a compound of Formula I. Therapeutically-effective, and thus leukotrieneantagonizing, dosages of from about 0.5 to 300 mg./kg.
per day, preferably 0.5 to 20 mg./kg., of the compound of Formula I be administered although it will, of course, readily be understood that the amount of the compound or compounds of Formula I actually to be administered will be determined by a physician, in the X-7387 -36light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
The pharmaceutical formulations of the present invention normally will consist of at least one compound of Formula I mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule, sachet, cachet, paper or other container or by a disposable container such as an ampoule. A carrier (or diluent) may be a solid, semi-solid or liquid material which serves as a vehicle, excipient or medium for the active therapeutic substance.
Some examples of the pharmaceutically-acceptable carriers which may be employed in the pharmaceutical formulation of the present invention are lactose, dextrose, sucrose, sorbitol, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoromethane and dichlorotetrafluoroethane. In the case of tablets, a lubricant 0 «B B~ n=l~iirsr_~-rur; X-7387 -37may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tableting machine. For such purpose there may be employed for instance aluminum, magnesium or calcium stearates, talc or mineral oil.
Preferred pharmaceutical formulations of the present invention are capsules, tablets, suppositories, injectable solutions, creams and ointments. Especially preferred are formulations for inhalation application, such as an aerosol, for oral ingestion and solutions for intravenous injection.
A preferred pharmaceutical invention of the instant invention comprises a therapeutically-effective amount of the preferred compounds of Formula I and a pharmaceutically-acceptable carrier, with the most preferred formulations comprising a therapeuticallyeffective amount of the compound of Example 24 (or a pharmaceutically-acceptable base-addition salt thereof) or the sodium salt of the compound of Example 24 and a pharmaceutically-acceptable carrier.
Preferred methods of treating a mammal suffering from or susceptible to any condition characterized by an excessive release of leukotrienes C 4
D
4 and E 4 which comprises administering to said mammal a leukotriene antagonizing amount of the compound of Example 24 (or a pharmaceutically-acceptable salt thereof), the sodium salt of the compound of Example 24, or a compound of the preferred compounds of Claim 1.
The following Examples and Preparations are provided merely to further illustrate the invention.
4~r a, r I i. ^11111111-~-_11- X-7387 -38- The scope of the inventon is not to be construed as merely consisting of the following Examples.
In the following Examples and Preparations, melting point, nuclear magnetic resonance spectra, high pressure liquid chromatography, ethyl acetate, N,Ndimethylformamide, methylethylketone, 1,2-dimethoxyethane and hexamethylphosphoramide are abbreviated n.m.r., HPLC, EA, DMF, MEK, DME, and HMPA, respectively. (The reported melting points are uncorrected).
Nuclear Magnetic Resonance spectra were obtained on a General Electric Model QE-300 300 MHz instrument or a Bruker 270 MHz instrument. HPLC were obtained on a Waters Associates Prep 500® Preparatory Scale HPLC equipped with PREPPAK® 500 silica columns.
Example 1 Ethyl 5-[(4-((4-acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(5valeroate) and the corresponding 1H-tetrazole-l-isomer l-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (15.0 g, 0.038 mol) was dissolved in DMF (150 ml).
Ethyl 5-bromovalerate (22.99 g, 0.11 mol) was added and the solution was stirred at room temperature for 2 days.
o The reaction mixture was poured into water and extracted (3X) with ethyl acetate. The ethyl acetate extract was washed with brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the concentrate was chromatographed by HPLC on a silica gel column 03 s X-7387 -39eluted isocratically with a 9:1 toluene:ethyl acetate mixture to yield the 2H-tetrazole-2-isomer in an 11.8 g yield. The eluting solvent was then changed to a 7:3 toluene:ethyl acetate mixture and the 1H-tetrazole-lisomer was obtained in a 4.0 g yield. The 2H-tetrazole- 2-isomer had the following properties: n.m.r. (300 MHz, CDC1 3 6: 1.0 3H); 1.24 3H); 1.6 4H); 2.04 2H); 2.36 2H); 2.6 3H); 2.61 2H); 4.13 2H); 4.2 2H); 4.6 2H); 5.08 2H); 6.9 2H); 7.0 1H); 7.25 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 27 Hs 5
N
4 0 5 Theory: C, 65.57; H, 6.93; N, 11.33; Found: C, 65.64; H, 6.92; N, 11.54.
The 1H-tetrazole-l-isomer had the following properties: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.24 3H); 1.6 4H); 1.8 2H); 2.25 2H); 2.64 3H); 2.7 2H); 4.12 4H); 4.24 2H); 5.08 2H); 6.91 2H); 7.0 1H); 7.14 2H); 7.62 2H); 12.66 1H).
Analysis Calculated for C 2 7 H3 4
N
4 0 5 Theory: C, 65.57; H, 6.93; N, 11.33; Found: C, 65.77; H, 7.03; N, 11.31.
Example 2 Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(4butyrate) and the corresponding 1H-tetrazole-l-isomer r X-7387 In a procedure similar to that of Example 1, the following reagents and amounts were combined: l-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (15.0 g, 0.38 mol); Ethyl 4-Bromobutyrate (21.4 g, 0.11 mol); and DMF (150 ml).
Isolation of the crude product and chromatography were done in the usual manner yielded 11.2 g of the 2H-tetrazole-2-isomer: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.25 3H); 1.6 2H); 2.35 4H); 2.63 3H); 2.7 2H); 4.13 2H); 4.18 2H); 4.64 2H); 5.06 2H); 6.9 2H); 7.0 1H); 7.15 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 26
H
32
N
4 0s: Theory: C, 64.98; H, 6.71; N, 11.66; Found: C, 65.13; H, 6.63; N, 11.50.
Chromatography also yielded 4.8 g of the 1H-tetrazole-l-isomer: n.m.r. (300 MHz, CDC13) 6: 3H); 1.26 3H); 1.6 2H); 2.06 2H); 2.32 2H); 2.62 3H); 2.64 2H); 4.14, 2H); 4.26 4H); 5.08 2H); 6.92 2H); 7.0 1H); 7.16 2H); 7.6 1H); 12.66 1H).
CuB~ _1C_ X-7387 -41- Analysis Calculated for C 26
H
3 2
N
4 0 5 Theory: C, 64.98; H, 6.71; N, 11.66; Found: C, 64.91; H, 6.74; N, 11.61.
Example 3 Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(2acetate) and the corresponding 1H-tetrazole-l-isomer In a procedure similar to that of Example 2, the following reagents and amounts were combined: 1-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (15.0 g, 0.38 mol); Ethyl 2-Bromoacetate (19.4 g, 0.11 mol); and DMF (150 ml).
The usual work-up and chromatography yielded 8.2 g of the 2H-tetrazole-2-isomer: n.m.r. (270 MHz, CDC1 3 6: 1.0 3H); 1.31 3H); 1.6 2H); 2.6 3H); 2.64 2H); 4.24 2H); 4.26 2H); 5.05 2H); 5.35 2H); 6.88 2H); 7.0 1H); 7.23 2H); 7.58 1H); 12.66 1H).
Analysis Calculated for C 24
H
28
N
4 0 5 Theory: C, 63.70; H, 6.24; N, 12.38; Found: C, 61.91; H, 6.23; N, 11.97.
r X-7387 -42- Chromatography also yielded 8.2 g of the IH-tetrazole isomer: 105 0 C; n.m.r. (270 MHz, CDC13) 6: 0.9 3H); 1.12 3H); 1.5 2H); 2.63 5H); 4.05 2H); 4.26 2H); 5.12 2H); 2H); 6.95 2H); 7.04 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 2 6H 32
H
4 Theory: C, 63.70; H, 6.24; N, 12.38; Found: C, 63.50; H, 5.96; N, 12.39.
Example 4 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-acetonitrile and the corresponding 1H-tetrazole-l-analog l-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (17.3 g, 0.045 mmol) was added to THF (200 ml). After stirring for 5 minutes, the mixture gelled. 0.5N Sodium hydroxide (1-2 ml) was added and the gel dissolved. 2- Bromoacetonitrile was added (6 g, 0.5 mol, 3.5 ml) and the reaction solution was heated to reflux temperature and stirred for 3 hours. The resultant precipitate was collected by filtration and the filtrate was reduced in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water and brine, dried over sodium sulfate, filtered, and the filtrate was taken to dryness and in vacuo. The resultant residue was chromatographed by HPLC on a silica gel au X- 7387 -43column, eluted first with toluene then a 9:1 toluene:ethyl acetate mixture after the forerunning compound had been eluted. The yield of the 2H-tetrazole- 2-isomer compound was 6.9 g: m.p. 101-103'C; n.m.r. (300 M~Hz, CDCl 3 6: 1.0 3H); 1.6 2H); 2.6 3H); 2.7 2H); 4.2 2H); 5.1 2H); 5.5 2H); 6.9 2H); 7.0 1H); 7.25 2H); 7.6 1H); 12.7 1Hi).
Analysis Calculated for C 2 2
H
2 3
N
5 03: Theory: C, 65.17; H, 5.72; N, 17.27; Found: C, 65.61; H, 5.56; N, 17.16.
The yield of the lH-tetrazole-l-isomer was 8.6 g; m.p. 89-92 0 C; n.m.r. (300 MHz, CDCl 3 6: 1.0 (t, 3H); 1.6 2H); 2.65 3H); 2.7 2H); 4.4 (s, 2H); 5.0 2H); 5.1 2H); 7.0 3H); 7.2 (d, 2H); 7.6 2H); 12.7 1H).
Analysis Calculated for C 22 H23 N 5 Theory: C, 65.17; H, 5.72; N, 17.27; Found: C, 65.34; H, 5.83; N, 17.02.
Example (4-Acetyl-3-hydroxy-2-propylphenyl methoxy)phenyl )methyl] -2-(3-bromopropyl )-2H-tetrazole and the corresponding 1-isomer l-[2-Hydroxy-3-propyl-4-( ylmtethyl )phenoxy)methyl )phenyl Iiethanorie sodium salt g, 0.039 mol) was added to THF (150 ml) and the h, X-7387 -44minimum amount of IN sodium hydroxide solution was added to effect solution. 1,3-Dibromopropane (12.12 g, 0.06 mol) was added and the reaction solution was stirred at room temperature for 24 hours. The reaction mixuture was concentrated in vacuo. Water was added to the concentrate and the resultant mixture was extracted with ethyl acetate The organic layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was chromatographed by HPLC on a silica gel column eluted with a mixture of 9:1 toluene:ethyl acetate to yield 3.0 g of a light yellow oil of the 2H-tetrazole-2-isomer of the above product.
Analysis Calculated for C 23
H
25
N
4 03Br: Theory: C, 56.68; H, 5.58; N, 11.50; Found: C, 56.84; H, 5.77; N, 11.59.
n.m.r. (300 MHz, CDCl 3 6: 1.0 3H); 1.6 2H); 2.5 2H); 2.6 3H); 2.65 2H); 3.4 (t, 2H); 4.2 2H); 4.75 2H); 5.15 2H); 6.9 (d, 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 (s, 1H).
The chromatography also yielded 2.0 g of the 1H-tetrazole-l-isomer: n.m.r. (300 MHz, CDC13) 6: 3H); 1.6 2H); 2.3 3H); 2.6 3H); 2.6 2H); 3.3 3H); 4.3 2H, t, 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.15 2H); 7.6 1H); 12.7 1H).
X-7387 Analysis Calculated for C 23
H
25
N
4 03Br: Theory: C, 56.68; H, 5.58; N, 11.50; Found: C, 58.60; H, 5.91; N, 11.93.
Example 6 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(4-butyronitrile) and the corresponding 1-isomer.
In a procedure similar to that of Example 4, 1-[2-hydroxy-3-propyl-4-((4-(lH-tetrazol-5-ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (17.3 g, 0.045 mol) was dissolved in THF (200 ml) then sodium hydroxide (1 ml) was added. 4-Bromobutyronitrile (7.4 g, 0.05 mol) was added and the reaction mixture was stirred at reflux temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water then dried over sodium sulfate, filtered and concentrated in vacuo.
The residue was chromatographed by HPLC on a silica gel column eluted with a gradient of toluene to 8:2 toluene: ethyl acetate to yield 9.9 g of the 2H-tetrazole-2-isomer: m.p. 82-84 0 C; n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.4 2H); 2.5 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.7 2H); 5.1 2H); 6.9 (d, 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
ii X-7387 -46- Analysis Calculated for C 2 4H 27
N
5 0 3 Theory: C, 66.50; H, 6.28; N, 16.16; Found: C, 66.76; H, 6.41; N, 16.29.
The chromatography also yielded 6.2 g of the 1H-tetrazole-l-isomer as an oil: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.1 2H); 2.4 (t, 2H); 2.65 3H); 2.7 2H); 4.25 2H); 4.3 (s, 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.1 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C 24
H
27 NO0 3 Theory: C, 66.50; H, 6.28; N, 16.16; Found: C, 67.12; H, 6.28; N, 15.75.
Example 7 5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-2H-tetrazole-2-(4-butyronitrile) 1-[2-Hydroxy-3-propyl-4-[[4-(H-tetrazol-5yl)phenoxy)methyl]phenyl]ethanone (10 g, 0.026 mol) was added to acetone (100 ml) and an excees of potassium carbonate (solid) was added. The reaction mixture was stirred for 30 minutes followed by the addition of 4-bromobutyronitrile (4.4 g, 0.03 mol). The resultant reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on i X-7387 -47- HPLC using the silica gel column eluted with a mixture of 9:1 toluene:ethyl acetate. This procedure yielded the title product: m.p. 108-110 0 C: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.4-2.6 4H); 2.6 3H); 2.7 2H); 4.8 2H); 5.2 2H); 7.0 (m, 3H); 7.6 1H); 8.1 2H); 12.7 1H).
Analysis Calculated for C 23
H
25
N
5 0 3 Theory: C, 65.86; H, 6.01; N, 16.70; Found: C, 66.16; H, 6.27; N, 16.05.
Example 8 5-[(4-((4-acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(5-valeronitrile) and the corresponding 1H-tetrazole-l-isomer In a procedure similar to that of Example 6, the following reagents and amounts were combined: l-[2-hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (17.3 g, 0.045 mol); THF (200 ml); sodium hydroxide solution (1 ml); and (8.1 g, 0.05 mol); X-7387 -48- After the usual work-up, the residue was chromatographed by HPLC on a silica gel column eluted with a gradient of neat toluene to a mixture of 7:3 toluene:ethyl acetate to yield the 2H-tetrazole-2-isomer as an oil (9.5 g): n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6-1.8 6H); 2.2 2H); 2.4 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.6 2H); 5.1 2H); 6.9 2H); 1H); 7.2 2H); 7.4 1H); 12.7 1H).
Analysis Calculated for C 25
H
29
N
5 0 3 Theory: C, 67.09; H, 6.53; N, 15.65; Found: C, 67.32; H, 6.48; N, 15.68.
The 1H-tetrazole-l-isomer was obtained as an oil n.m.r. (300 MHz, CDCl 3 6: 1.0 3H); 1.5-1.7 6H); 1.9 2H); 2.3 2H); 2.65 3H); 2.7 2H); 4.1 2H); 4.3 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.1 2H); 7.6 1H); 12.7 (s, 1H).
r~'lysis Calculated for C 2 sH 29
N
5 0 3 Theory: C, 67.09; H, 6.53; N, 15.65; Found: C, 67.28; H, 6.79; N, 15.48.
X-7387 -49- Example 9 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(5-bromopentanyl)-2H-tetrazole In a procedure similar to Example 5, the following reagents and amounts were combined.
1-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (10 g, 0.026 mol); (6.9 g, 0.03 mol); Potassium carbonate (5 and MEK (150 ml).
The above reaction mixture was stirred at room temperature for 48 hours. Work-up and chromatography were as with Example 5 to yield 4.2 g, 31.3% yield of the 2H-tetrazole-2-isomer of the title product as a light yellow oil: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 2H); 1.6 2H); 1.9 2H), 2.0 2H); 2.6 (s, 3H); 2.7 2H); 3.4 2H); 4.2 2H); 4.55 (t, 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C 25
H
31
N
4 03Br: Theory: C, 58.25; H, 6.06; N, 10.87; Found: C, 58.13; H, 6.13; N, 10.64.
X-7387 Example 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(6-hexanenitrile) 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(5-bromopentanyl)-2H-tetrazole (3.9 g, 0.0075 mol) was dissolved in DMSO (30 ml).
Potassium cyanide (0.975 g, 0.015 mol) was added and the reaction was slurried at room temperature for 6 hours.
Water (250 ml) was added to the slurry and the mixture was extracted with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed by HPLC on a silica gel column eluted with a mixture 9:1 toluene:ethyl acetate to yield 2.7 g, 77.1% yield of the title (2H-tetrazole-2-isomer) product: n.m.r. (300 MHz, CDC1 3 6: 1.0 3H); 1.5 2H); 1.6 2H); 1.7 2H); 2.05 2H); 2.3 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.6 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C 28
H
37 N0 3 Theory: C, 67.66; H, 6.77; N, 15.15; Found: C, 67.80; H, 6.80; N, 14.99.
L -u X-7387 -51- Example 11 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(7-heptanenitrile) In a procedure similar to Example 7, the following reagents and amounts were used: l-[2-Hydroxy-3-propyl-4-((4-(1H-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (10 g, 0.026 mol); MEK (100 ml); potassium carbonate: (5 and 7-bromoheptanonitrile (5.7 g, 0.03 mol).
The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was worked up in the usual way. The residue was chromatographed by HPLC on a silica gel column, eluted with a mixture of 8:2 toluene: ethyl acetate to yield 2.7 g of the 2H-tetrazole-2-isomer as a light yellow oil: n.m.r.
(300 MHz, CDCls) 6: 1.0 3H); 1.4 2H); 1.5 (m, 2H); 1.8 4H); 2.0 2H); 2.3 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.6 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 (s, 1H).
X-7387 -52- Analysis Calculated for C27H 33
N
5 0 3 Theory: C, 68.19; H, 6.99; N, 14.73; Found: C, 68.34; H, 7.20; N, 14.49.
Example 12 5-[(4-((4-Acetyl-3-hydroxy-2-ethylphenyl)methoxy)phenyl)methyl]-2-(6-bromohexyl)-2H-tetrazole The following reagents and amounts thereof were combined in acetone (50 ml): l-[2-Hydroxy-3-ethyl-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone (8.5 g, 0.0241 mol); 1,6-dibromohexane (7.32 g, 0.03 mol); and Potassium carbonate (5.3 g, 0.004 mol); The above mixture was stirred for 24 hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with dilute sodium hydroxide solution, dried over magnesium sulfate, and concentrated in in vacuo.
The residue was chromatographed by HPLC on a silica gel column eluted first with toluene then a with a mixture of 5% ethyl acetate in toluene. From the chromatography was collected the fractions containing 4 g of the 2H-tetrazole-2-isomer of the title product as an oil: X-7387 -53n.m.r. (300 MHz, CDCl 3 6: 1.18 3H); 1.32 (in, 2H); 1.48 (in, 2H); 1.83 (mn, 2H); 2.0 (in, 2Hi); 2.62 3H); 2.72 2H); 3.38 2H); 4.2 2H); 4.56 2H); 5.06 2H); 6.91 2H); 7.0 1H1); 7.24 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 25
H
3 lN 4
O
3 Br: Theory: C, 58.75; H, 6.00; N, 10.82; Found: C, 58.42; H, 6.19; N, 10.72.
Example 12A (4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl )methyl-2- (6-bromohexyl )-2H-tetrazole In a procedure similar to that of Example 12 above, the following reagents and amounts were combined: 1- [2-Hydroxy-3-propyl-4-( (4-(1H-tetrazol-5ylmethyl )phenoxy )iethyl )phenyl Iethanone sodium salt (7.82 g, 0.02 mol); 1,6-dibromohexane (4.88 g, 0.02 mol); Acetonitrile (100 ml); and 1IMPA (50 ml).
c i- X-7387 -54- The above mixture was stirred at room temperature for 48 hours then the crude product was isolated and chromatographed as in Example 12. This procedure yielded 3.7 g of the 2H-tetrazole-2-isomer: n.m.r. (300 MHz, CDC1 3 6: 1.0 3H); 1.34 2H); 1.48 2H); 1.6 2H); 1.83 2H); 2.0 2H); 2.6 3H), 2.66 2H); 3.36 2H); 4.2 2H); 4.56 2H); 5.08 2H); 6.9 2H); 7.0 1H); 7.21 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 26
H
33
N
4 03Br: Theory: C, 58.98; H, 6.28; N, 10.58; Found: C, 59.95; H, 6.47; N, 10.41.
Example 13 5-[(4-((4-Acetyl-3-hydroxy-2-ethylphenyl)- 1. methoxy)phenyl)methyl]-2H-tetrazol-2-(6-heptanonitrile) 5-[(4-((4-Acetyl-3-hydroxy-2-ethylphenyl)methoxy)phenyl)methyl]-2-(6-bromohexyl)-2H-tetrazole (3.7 g, 0.0072 mol) and sodium cyanide (7.2 g) were dissolved in DMSO (25 ml). The mixture was stirred at room temperature for 1 hour then diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed three times with water then dried over sodium sulfate. The dried extracts were taken to dryness in vacuo to leave 3.2 g of a residue of the title (2H-tetrazole) product: n.m.r. (300 MHz, CDC13) 6: 1.18 3H); 1.36 2H); 1.5 2H); X- 7387 1.65 (in, 2H); 2.02 (mn, 2H); 2.32 2H); 2.63 3H); 2.72 2H); 4.2 2H); 4.56 2H); 5.06 2H); 6.90 2H); 7.0 1H); 7.26 2H); 7.6 1H); 12.65 1H).
Analysis Calculated for C 26
H
31
N
5 0 3 Theory: C, 66.79; H, 6.95; N, 15.58; Found: C, 65.54; H, 6.23; N, 14.26.
Example 14 ((4-Acetyl-3-hydroxy-2-propylphenyl methoxy)phenyl)methyl]-2H-tetrazole-2-(5-(2 ,2-dimethylpentanenitrile)) and the corresponding lH-tetrazole- 1-isomer In a procedure similar to that of Example 11, the following reagents and amounts were combined: 1- [2-Hydroxy-3-propyl-4-( ylmethyl )phenoxy )methyl )phenyl] ethanone sodium salt (9.3 g, 0.024 mol); MEK (100 ml); potassium carbonate: (4 g, .024 mol); (4-cyano-3,3-diinethyl)butyl iodide (5.7 g, 0.024 inol).
I X-7387 -56- The above reaction mixture was stirred at room temperature for 24 hours. After the usual work-up, the residue was chromatographed on HPLC on a silica gel column eluted with a mixture of 9:1 toluene:ethyl acetate. The chromatography yielded the 2H-tetrazole-2-isomer of the above title product as an oil: n.m.r. (300 MHz, CDC13) 6: 3H); 1.15 6H); 1.6 2H); 2.1 2H); 2.3 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.6 (t, 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C27H 33 NsO 3 Theory: C, 68.19; H, 6.99; N, 14.73; Found: C, 68.40; H, 7.27; N, 14.51.
The chromatography also yielded the 1H-tetrazole isomer of the above title product as an oil: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.1 6H); 1.6 2H); 1.7 (t, 2H); 2.15 2H); 2.6 3H); 2.7 2H); 4.15 (t, 2H); 4.25 2H); 5.1 2H); 6.9 2H); 7.0 (d, 1H); 7.2 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C 27
H
33
N
5 0 3 Theory: C, 68.19; H, 6.99; N, 14.73; Found: C, 70.28; H, 7.29; N, 13.42.
1-11-L IIIIII~L---l1~ X-7387 -57- Example 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-(dimethylamino)propyl)-2Htetrazole In a procedure similar to that of Example 17 the following reagents and amounts were combined: 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-bromopropyl)-2H-tetrazole (3 g, 0.006 mol); Acetonitrile (50 ml); and Dimethylamine (large excess) The mixture was cooled and stirred at 0 C for 5 hours. The crude product was isolated and chromatographed as in Example 14, with the exception that the eluant was a 9.5:0.5 methylene chloride:methanol mixture containing an additional 0.5% of diethylamine. The procedure yielded 2.4 g, 88.9% yield of the title (2Htetrazole-2-isomer) product as a yellow oil: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.1 (m 2H); 2.2 6H); 2.3 2H); 2.6 3H); 2.65 2H); 4.2 (s, 2H); 4.6 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
I 1.
X-7387 -58- Analysis Calculated for C 25
H
33 NsO 3 Theory: C, 66.50; H, 7.37; N, 15.51; Found: C, 66.71; H, 7.28; N, 15.58.
Example 16 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-l-(3-(dimethylamino)propyl)- 1H-tetrazole 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-l-(3-bromopropyl)-lH-tetrazole g, 0.004 mol) was added to acetonitrile (40 ml).
Dimethylamine (large excess) was cooled in the unopened reagent bottle then added to the acetonitrile solution.
The mixture was cooled and stirred at 0 C for 5 hours then concentrated in vacuo. Water was added to the concentrate and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted isocratically with a mixture of 9.5:0.5% methylene chloride:methanol plus 0.5% diethylamine added) to yield 1.4 g, 77.8% yield of the title product as a yellow oil; n.m.r. (300 MHz, CDC1 3 6: 1.0 3H); 1.6 2H); 1.9 2H); 2.1 6H; m, 2H); 2.6 (s, 3H); 2.65 2H); 4.2 2H); 4.3 2H); 5.1 (s, 2H); 6.9 2H); 7.0 1H); 7.15 2H); 7.6 (d, 1H); 12.7 1H).
X-7387 -59- Analysis Calculated for C 25
H
33
N
5 0 3 Theory: C, 66.50; H, 7.37; N, 15.51; Found: C, 66.74; H, 7.22; N, 15.59.
Example 17 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-methylthiopropyl)-2Htetrazole 4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-bromopropyl)-2H-tetrazole (3.1 g, 0.006 mol) was dissolved in DMSO (20 ml). A large excess of sodium methyl sulfide was added and the reaction mixture was stirred at room temperature for three hours. Water (100 ml) was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 2.1 g, 77.8% yield of the title product as a yellow oil which crystallized upon standing: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.1 3H); 2.3 (m, 2H); 2.5 2H); 2.6 3H); 2.7 2H); 4.2 2H); 4.7 2H); 5.1 1H); 6.9 2H); 7.0 1H); 7.3 2H); 7.6 1H); 12.7 1H).
_I i i i n i i X-7387 Analysis Calculated for C 24
H
30
N
4 0 3
S:
Theory: C, 63.41; H, 6.65; N, 12.32; Found: C, 63.62; H, 6.70; N, 12.70.
Example 18 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(a-(p-tolunitrile)) In a procedure similar to that of Example 11, the following reagents and amounts were combined: l-[2-Hydroxy-3-propy'.-4-((4-(lH-tetrazol-5ylmethyl)phenoxy)methyl)phenyl]ethanone (11 g, 0.03 mol); acetone (100 ml); potassium carbonate (6.9 g, 0.05 mol); and a-bromo-p-tolunitrile (6.3 g, 0.032 mole).
The above mixture was stirred for 72 hours at 0 C and the crude product isolated in the usual manner.
The residue was chromatographed by HPLC over silica using a toluene 5% ethyl acetate mixture to yield the 2H-tetrazole-2-isomer (5.0 n.m.r. (300 MHz, CDCl 3 6: 3H); 1.6 2H); 2.62 3H); 2.66 2H); 4.2 2H); 5.08 2H); 5.76 2H); 6.9 2H); 7.0 1H); 7.23 4H); 7.43 2H); 7.6 1H); 7.68 2H); 12.66 1H).
X-7387 -61- Analysis Calculated for C 28
H
27
N
5 0 3 Theory: C, 69.84; H, 5.65; N, 14.54; Found: C, 70.85; H, 5.94; N, 13.43.
Example 19 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)]-2-(3-bromopropyl)-2H-tetrazole l-[2-Hydroxy-3-propyl-4-((4-(lH-tetrazol-5yl)phenoxy)methyl)phenyl]ethanone sodium salt (5 g, 0.013 mol), 1,3-dibromopropane (3.5 g, 0.18 mol), and MEK (50 ml) were combined potassium carbonate (4.15 g, 0.025 mol) potassium was added and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The volume of the concentrate was doubled by the addition of water and the resultant solution was extracted with ethyl acetate The ethyl acetate layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a mixture of 9:1 toluene:ethyl acetate) to yield 5.0 g, 82% yield of the title product: n.m.r. (300 MHz CDC13) 6: 1.0 3H); 1.6 2H); 2.6 (s and t, 5H); 2.7 2H); 3.5 2H); 4.8 2H); 5.15 2H); 7.1 2H); d, 1H); 7.6 1H); 8.1 (d, 2H); 12.7 1H).
Analysis Calculated for C 22
H
2 sN 4 03Br: Theory: C, 55.82; H, 5.32; N, 11.84; Found: C, 55.95; H, 5.28; N, 11.76.
X-7387 -62- Example 5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-2H-tetrazole-2-(4-butyronitrile) 5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-lH-tetrazole (10 g, 0.026 mol) was added to acetone. Potassium carbonate (excess) was added to the solution and the mixture was stirred at room temperature for 30 minutes. 4-Bromobutyronitrile (4.44 g, 3 ml, 0.03 mol) was added and the mixture was stirred overnight at room temperature. Water was added and the resultant mixture was extracted with ethyl acetate. The ethyl acetate layers were treated and chromatographed as in Example 19 to yield 4.8 g, 43.6% yield of the title product: 108-110 0 C; n.m.r. (300 MHz, CDC13) 6: 3H); 1.6 2H); 2.4-2.6 (two sets of multiplets, 4H); 2.6 3H); 2.7 2H); 4.8 2H); 5.2 2H); 7.0-7.1 (two d, 3H); 7.6 1H); 8.1 2H); 12, (s, 1H).
Analysis Calculated for C 23
H
25 NsO 3 Theory: C, 65.86; H, 6.01; N, 16.07; Found: C, 66.16; H, 6.27; N, 16.50.
I. i I X-7387 -63- Example 21 l-[2-Hydroxy-3-propyl-4-[[4-[[l-(lH-tetrazolethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-lH-tetrazole-l-(acetonitrile) (8.6 g, 0.021 mol) was dissolved in DME (100 ml).
Tri(n-butyl)tin azide (21.1 g, 0.063 mol) was added and the reaction mixture was stirred and heated at reflux temperature for 3 days. The reaction mixture was cooled and poured into a 50/50 toluene/dilute hydrochloric acid solution (1 liter). The acidified mixture was stirred for several hours, yielding an oil. The solvent was decanted from the oil. The oil was dissolved in ethanol then the ethanol was removed in vacuo. (The ethanol procedure was repeated once). The residue was dissolved in ethyl acetate (200 ml) and hexane was added to the solution until it became cloudy. Upon standing, a precipitate formed from the cloudy solution, the precipitate was collected by filtration to yield 7.7 g of the title product: 1480-1500C; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 3H); 1.5 2H); 2.6-2.8 (m overlapping peaks 5H); 4.3 2H); 5.1 2H); 6.1 2H); 6.9 2H); 7.1 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 22
H
24
N
8 0 3 Theory: C, 58.92; H, 5.37; N, 24.99; Found: C, 59.20; H, 5.44; N, 24.72.
X-7387 -64- Example 22 1-[2-hydroxy-3-(propyl)-4-[[4-[[2-(IH-tetrazol-5-ylmethyl)-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(acetonitrile) (6.9 g, 0.017 mol) was dissolved in DME (100 ml).
Tri(n-butyl)tin azide (17 g, 0.05 mol) was added and the reaction mixture was stirred and heated to reflux temperature for 3 days. The reaction mixture was cooled and poured into a 50/50 mixture of dilute aqueous hydrochloric acid and toluene. The resultant oil was collected and precipitated from a mixture of ethyl acetate/hexane to yield 2.3 g of the title product: m.p.
137 0 -139 0 C; (300 MHz, DMSO-d6) 6: 0.9 3H); 2H); 2.6-2.7 (s and t overlapping, 5H); 4.2 (s, 2H), 5.2 2H); 6.4 2H); 6.9 2H); 7.1 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 22
H
24 N80 3 Theory: C, 58.92; H, 5.39; N, 24.99; Found: C, 59.15; H, 5.41; N, 24.74.
I, X-7387 Example 23 l-[2-Hydroxy-3-propyl-4-[[4-[[l-[3-(1Hphenyl]ethanone 5-T(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-IH-tetrazole-l-(4-butyronitrile) (6.2 g, 0.014 mol) was dissovled in DME (100 ml).
Tri(n-butyl)tin azide (14.5 g, 0.043 mol) was added and the reaction mixture was stirred at reflux temperature for 3 days then cooled to room temperature. The reaction mixture was poured into a 50/50 mixture of toluene/dilute aqueous hydrochloric acid and the resultant mixture was stirred for 1 hour. The oil thus obtained was isolated by decanting the solvents. The oil was twice dissolved in ethanol and taken to dryness. The residue was dissolved in ethyl acetate (150 ml). Hexane was added to the ethyl acetate solution until the the solution became cloudy. Upon standing an oil resulted. The oil was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a gradient of neat methylene chloride to a mixture of 9:1 methylene chloride:methanol).
The resultant product-containing fractions were combined and taken to dryness. The residue was dissolved in ethyl acetate. Hexane was added to the solution to the point of cloudiness. An oil formed upon standing and the solution was cooled in the refrigerator overnight.
A solid formed when the cooled solution was stirred.
The solid was collected by filtration. The solid was r l* -f t I I_ X-7387 -66the title product: m.p. 121 0 -123 0 C; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 3H); 1.5 2H); 2.5 2H); 2.6 (s and t, 5H); 2.9 2H); 4.3 1H); 4.5 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 2 4H2 8
N
8 0 3 Theory: C, 60.49; H, 5.92; N, 23.51; Found: C, 60.47; H, 5.81; N, 23.51.
Example 24 1-[2-Hydroxy-3-propyl-4[[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(4-butyronitrile) (7 g, 0.016 mol) was dissolved in DME (50 ml). Tri(nbutyl)tin azide (16.3 g, 0.048 mol) was added and the reaction mixture was stirred and heated to reflux temperature for 3 days. The reaction mixture was cooled to room temperature and poured into a mixture of aqueous hydrochloric acid (125 ml/- 125 ml/ (25 ml in 225 The resultant precipitate was collected by filtration and recrystallized from a mixture of ethanol and water to yield 5.6 g, 71.8% yield of the title product: m.p 118-121 0 C; n.m.r. (300 MHz, DMSO-dG) 6: 0.9 3H); 1.5 2H); 2.4 2H); 2.6-2.7 3H; t, 2H); 2.9 2H); 4.1 2H); 4.7 2H); 5.1 2H); 6.9 2H); 7.1 1H); 7.2 (d, 2H); 7.8 1H); 12.7 1H). i i I X-7387 -67- Analysis Calculated for C 24
H
28
N
8 0 3 Theory: C, 60.49; H, 5.92; N, 23.52; S Found: C, 60.88; H, 5.85; N, 23.51.
5 The sodium salt was formed by dissolving the above free tetrazole (12.55 g, 0.0263 mol) in ethanol.
lN sodium hydroxide solution (26.3 ml) was added and the solution was stirred for 30 minutes). The solvent was removed in vacuo. A foam formed which was dried under vacuum at 30-40 0 C and was 11.8 g, 85.3% yield of the sodium salt of the title compound: m.p. 85-90°C; n.m.r.
(300 MHz, DMSO-d 6 6: 0.9 3H); 1.4-1.6 2H); 2.2 2H); 2.6-2.8 (overlapping peaks 7H); 4.2 2H), 4.7 2H); 5.1 2H); 6.9 2H); 7.0 1H) 7.2 2H); 7.8 1H); 12.7 1H).
SAnalysis Calculated for C 24
H
27 N80 3 Na: Theory: C, 57.82; H, 5.46; N, 22.48; Found: C, 57.24; H, 5.79; N, 21.46.
Example 1-[2-Hydroxy-3-propyl-4-[[4-[[1-[4-1H-tetraphenyl]ethanone and the corresponding sodium salt 5-[(4-((4-Acetv 3-hydroxy-2-propylphenyl)- (6.7 g, 0.015 mol) was dissolved in DME (100 ml).
Tri(n-butyl)tin azide (15.2 g, 0.045 mol) was added then the reaction mixture was heated to reflux tempera- I
-A
X-7387 -68ture and stirred for 3 days. The mixture was cooled and poured into a 1:1 mixture of toluene:10% aqueous hydrochloric acid solution. The resultant mixture was stirred for several days until a precipitate formed.
The precipitate was collected by filtration and recrystallized from a mixture of ethyl acetate:hexane to yield 3.6 g, 49% of the title product: 96-98 0 C; n.m.r.
(300 MHz, DMSO-d 6 6: 0.9 2H); 1.5 2H); 1.6-1.8 (overlapping peak, 6H); 2.6-2.7 (overlapping peaks, 2.75 2H); 4.3 2H); 4.4 2H); 5.1 2H); 2H); 7.05 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 25
H
30
N
8 0 3 Theory: C, 61.21; H, 6.16; N, 22.84; Found: C, 60.98; H, 6.05; N, 22.71.
Example 26 l-[2-Hydroxy-3-propyl-4-[[4-[[2-[4-(1H-tetraphenyl]ethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(5-valeronitrile) g, 0.02 mol) was dissolved in DME (100 ml).
Tri(n-butyl)tin azide (21.6 g, 0.06 mol) was added and the reaction mixture was heated to reflux temperature and stirred for 3 days. The reaction mixture was cooled and poured into a 1:1 mixture of toluene: 10% aqueous I_ X-7387 -69hydrochloric acid. After stirring for 2 hours, the organic phase was separated, dried over sodium sulfate and taken to dryness in vacuo. The resultant residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a gradient of neat methylene chloride to a mixture of 9:1 methylene chloride:methanol).
The product-containing fractions were combined and concentrated then dissolved in ethyl acetate. Hexane was added to the ethyl acetate solution until the solution became cloudy. An oil formed from the cloudy solution. The mixture was stored overnight in the refrigerator resulting in a precipitate (6.3 g, 64.3%) of the title product: 119-123"C; n.m.r. (300 MHz, DMSO-d 6 6 0.9 3H); 1.55 2H); 1.7 2H); 1.95 2H); 2.8 (overlapping peaks, 5H); 2.9 2H); 4.15 2H); 4.7 2H); 5.1 2H); 6.9 2H); 7.1 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis Calculated for C 25
H
30
N
8 0 3 Theory: C, 61.21; H, 6.16; N, 22.84; Found: C, 61.03; H, 6.31; N, 22.62.
Example 27 1-[2-Hydroxy-3-propyl-4-[[4-[[2-[6-(lHtetrazol-5-yl)hexyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(7-heptanenitrile) (2.4 g, 0.005 mol) was dissolved in glyme. Tri(n-butyl) i I, c. i X-7387 tin azide (5.12 g, 0.015 mol) was added and the reaction mixture was heated to reflux temperature and stirred for 3 days. The reaction mixture was cooled to room temperature and poured into a 1:1 mixture of aqueous hydrochloric acid. The acidic mixture was stirred for 2 hours resulting in a precipitate. The precipitate was filtered and recrystallized from a mixture of ethanol and water to yield 1.0 g of the title product: 110 0 -113 0 C; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 3H); 1.2-1.4 2H; m, 2H); 1.5 2H); 1.7 2H); 1.9 2H); 2.6-2.7 3H, t, 2H); 2.8 (t, 2H); 4.1 2H); 4.6 2H); 5.1 1H); 6.9 overlapping 2H); 7.1 2H); 7.2 2H); 7.8 2H); 12.7 1H); Analysis Calculated for C 2 7
H
3 4
N
8 0 3 Theory: C, 62.53; H, 6.61; N, 21.61; Found: C, 62.73; H, 6.83; N, 21.63.
Example 28 l-[ 4 -[[4-[[2-[3,3-Dimethyl-4-(lH-tetrazol- 5-yl)butyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]-2hydroxy-3-propylphenyl]ethanone 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(5-(2,2-dimethylpentanenitrile)) (4.2 g, 0.008 mol) was dissolved in diglyme (35 ml). Tri(n-butyl)tin azide (8.6 g, 0.025 mol) was added and the reaction mixture was heated to I_ 4_1_1 X-7387 -71reflux temperature and stirred for 3 days. The mixture was cooled to room temperature and poured into a 1:1 mixture of toluene/hexane:10% aqueous hydrochloric acid (250 ml). An oil resulted from the acidic mixture.
The oil was isolated by decanting the solvent. The oil was dissoved in ethanol then the ethanol solution was evaporated to dryness. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a gradient of neat methylene chloride to a mixture of 9:1 methylene chloride:methanol) to yield 1.5 g, 38.9% yield of the title product as an oil: n.m.r. (300 MHz, DMSO-d 6 6: 1.0 3H); 1.1 6H); 1.6 2H); 2H); 2.6 3H); 2.7 2H); 2.9 2H); 4.2 (s, 2H); 4.7 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.2 2H); 7.6 1H); 12.7 1H).
Analysis Calculated for C 2 7
H
34
N
8 0 3 Theory: C, 62.53; H, 6.61; N, 21.61; Found: C, 62.38; H, 6.40; N, 21.40.
Example 29 1-[2-Hydroxy-3-propyl-4-[[4-[[2-[5-(IH-tetrazol-5-yl)pentyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone sodium salt 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(6-hexanenitrile) g, 0.005 mol) was dissolved in DME. Tri(n-butyl)tin azide (5.5 g, 0.016 mol) was added and the mixture was X-7387 -72stirred and heated at reflux temperature for 3 days.
The reaction mixture was cooled to room temperature and poured into a mixture of 1:1 toluene/hexane:10% aqueous hydrochloric acid solution (200 ml). The acidic mixture yielded an oil. The solvent was-poured from the mixture and the oil thus isolated was dissolved in ethanol. The ethanol solution was taken to dryness and the resultant residue was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with a gradient of neat methylene chloride to a mixture of 9:1 methylene chloride/methanol). The chromatography yielded a 1.3 g, 51.6% yield of an oil of the free acid title product.
The sodium salt of the above title product was formed by first dissolving the above oil composed of the free acid in ethanol. lN Sodium hydroxide solution n (2.6 ml) was added, then the solvent was removed in Svacuo. A foam formed which was dried under vacuum at 30-40°C to yield 1.4 g of the sodium salt of the title product: m.p. 70 0 -80 0 C; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 So 20 3H); 1.3 2H); 1.5-1.7 4H); 1.9 2H); 2.6 2H); 2.7 3H; t, 2H); 4.1 2H); 4.6 2H); 5.1 2H); 6.9 2H); 7.0 1H); 7.2 2H); 7.8 2H); 12.7 1H).
Analysis Calculated for C 26
H
32 N80 3 Na: Theory: C, 59.30; H, 5.93; N, 21.28; o Found: C, 59.76; H, 5.93; N, 20.68.
0 '3 0 X-7387 -73- Example 5-[[4-[(4-Acetyl-3-hydroxy-2-propylphenyl)methoxy]phenyl]methyl]-lH-tetrazole-l-acetic acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-(n-propyl)phenyl)methoxy)phenyl)methyl]-1H-tetrazole-l-(2-acetate) (7.7 g, 0.017 mol) and 5N aqueous sodium hydroxide solution (10 ml) were combined, stirred, and heated to reflux temperature. Methanol (50 ml) was added to the solution after the mixture began to reflux. After 1 hour at reflux temperature, the solution was poured into water and the resultant solution was made acidic by the addition of aqueous hydrochloric acid. The acidified solution was allowed to stand overnight then made basic with 5N sodium hydroxide solution. The aqueous layer was separated and made acidic again by the addition of aqueous hydrochloric acid. The acidified aqueous layer was extracted with a mixture of 2:1 ether:isopropyl alcohol. The organic phase was separated and then taken to dryness. The resultant residue was disso'ved in the minimum amount of hot DMF. Water was added to the DMF solution to induce crystallization and the mixture was allowed to stand overnight. The precipitate was collected by filtration and washed with ethanol. The collected precipitate was then dried in a vacuum oven at 0 C. This procedure yielded 2.8 g of the title product: 205-210 0 C. n.m.r. (270 MHz, DMSO-d 6 6: 0.95 (t, 3H); 1.5 2H); 2.63 5H); 4.24 2H); 5.12 (s, 2H); 5.38 2H); 6.94 7.04 1H); 7.2 (d, S2' 2H); 7.8 1H); 12.7 1H).
i ii i i_ I X-7387 -74- Analysis Calculated for C 22
H
24
N
4 0 5 Theory: C, 62.25; H, 5.70; N, 13.20; Found: C, 62.22; H, 5,94; N, 12.98.
Example 31 5-[[4-[(4-Acetyl-3-hydroxy-2-propylphenyl)methoxy]phenyl]methyl]-2H-tetrazole-2-acetic acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(2-acetate) g, 0.017 mol) absolute ethanol (100 ml), and aqueous sodium hydroxide solution (5N, 10 ml) were combined, stirred and heated to reflux temperature.
After 1 hour the reaction solution was poured into water and the resultant solution was made acidic by the addition of 5N hydrochloric acid. After standing overnight, the acidic solution was extracted with ethyl acetate and the organic layer was dried over a mixture of sodium sulfate and magnesium sulfate. The organic layer was then evaporated in vacuo to an oil that yielded some crystals on standing. The mixture was chromatographed by HPLC (preparatory-scale, silica gel column, eluted with 2:8 methanol:methylene chloride solvent system) to yield two products in fractions 3-6. These fractions were combined, and the solvent was removed. The residue was heated in 20 ml of EtOH and 2.5 mL 5N NaOH for 3 hours. After cooling, the reaction mixture was diluted with lN hydrochloric acid (to a total volume of 50 ml).
The resultant precipitate was collected by filtration.
I-
I s- X-7387 The precipitate was recrystallized from 90% EtOH (H 2 0) to yield 0.6 g of title product: m.p. 87-90 0 C: n.m.r.
(300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.62 (s, 3H); 2.64 2H), 4.22 2H), 5.06 2H), 5.42 2H); 6.9 2H), 7.0 1H); 7.24 2H); 7.6 (d, 1H); 12.64 1H).
Analysis Calculated for C 22
H
24
N
5 0 4 Theory: C, 62.25; H, 5.70; N, 13.20; Found: C, 62.12; H, 5.83; N, 12.95.
Example 32 5-[[4-[[4-Acetyl-3-hydroxy-2-propylphenyl)methoxy]phenyl]methyl]-H-tetrazole-l-butyric acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-1H-tetrazole-l-(4-butyrate) (4.8 g, 0.010 mol) was dissolved in 2B absolute ethanol and aqueous sodium hydroxide solution (5N, 6 ml) was added. The solution was stirred and heated to reflux temperature for 2 hours then cooled to room temperature.
The cooled reaction solution was poured into water and the resultant solution was made acidic with the addition of concentrated hydrochloric acid. The acidified solution was extracted with ethyl acetate and the ethyl acetate layers were dried over sodium sulfate/silicone dioxide, filtered and taken to dryness in vacuo. The resultant residue was chromatographed by HPLC (preparatory-scale, silica gel column, 5% methanol in methylene chloride) to yield 2.4 g of the title product: X-7387 -76- 106-108 0 C. n.m.r. (300 MHz, CDC13) 6: 0.96 3H); 1.58 2H); 2.05 2H); 2.34 2H); 2.60 3H); 2.64 2H); 4.22 4H); 5.05 2H); 6.9 2H); 6.98 1H); 7.12 2H); 7.6 1H); 12.66 1).
Analysis Calculated for C 24 H2 8
N
4 0 5 Theory: C, 63.70; H, 6.24; N, 12.38; Found: C, 63.48; H, 6.13; N, 12.16.
Example 33 5-[(4-[(4-Acetyl-3-hydroxy-2-propylphenyl)methoxyJphenyl)methyl]-2H-tetrazole-2-butanoic acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(4-butyrate) (11.2 g, 0.0233 mol) was dissolved in 2B absolute ethanol. To the solution was added aqueous sodium hydroxide solution (14 ml, 5N) and the solution was heated to reflux and stirred for 2 hours. The reaction mixture was cooled and poured into water and the resultant solution was made acidic with concentrated hydrochloric acid. The acidic solution was allowed to stand overnight and the resultant solid was collected by vacuum filtration.
The solid was dried in vacuo at 40 0 C. The dried solid was recrystallized from ethanol, filtered, and dried in vacuo to yield 7.8 g of the title product: 92-940C.; n.m.r. (300 MHz, DMSO-d 6 6: 0.92 3H); 1.52 2H); 2.1 2H); 2.26 2H); 2.62 5H); 4.16 2H); 4.66 2H); 5.15 2H); 6.95 2H); 7.05 1H); 7.2 2H); 7.8 1H); 12.7 H).
C1 o X-7387 -77- Analysis Calculated for C 24
H
28
N
4 0 5 Theory: C, 63.70; H, 6.24; N, 12.38; Found: C, 63.75; H, 6.34; N, 12.70.
Example 34 5-[(4-[(4-Acetyl-3-hydroxy-2-propylphenyl)methoxy]phenyl)methyl]-lH-tetrazol-l-valeric acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylg, 0.0081 mol) was dissolved in 2B ethanol. Sodium hydroxide solution (5N, 5 ml) was added and the solution was stirred at reflux temperature for 2 hours. The solution was cooled to room temperature, poured into water, and the resultant solution was made acidic with concentrated hydrochloric acid. The acidified solution was extracted with ethyl acetate The ethyl acetate layers were combined and dried over of sodium sulfate/silicon dioxide, filtered and evaporated to dryness in vacuo. The residue was chromatographed by HPLC (preparatory-scale, silica gel column, 5% methanol in methylene chloride) to give 2.7 g of the title product: n.m.r. (300 MHz, CDC13) 6: 0.98 3H); 1.56 4H); 1.76 2H); 2.3 2H); 2.62 3H); 2.64 2H); 4.13 2H); 4.24 2H); 5.08 2H); 6.9 2H); 6.98 1H); 7.12 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 2 5
H
30
N
4 0 5 Theory: C, 64.36; H, 6.48; N, 12.01; Found: C, 63.05; H, 6.72; N, 11.03.
L -i 1 X-7387 -78- Example 5-[(4-[(4-Acetyl-3-hydroxy-2-propylphenyl)methoxy]phenyl)methyl]-2H-tetrazole-2-valeric acid Ethyl 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2H-tetrazole-2-(5-valerate) (11.8 g, 0.0239 mol) was dissolved in 2B absolute ethanol. Aqueous sodium hydroxide solution (5N, 14.3 ml) was added to the solution and the solution was stirred at reflux temperature for 2 hours. The crude product was isolated from the reaction mixture as in Example 34 and chromatographed by HPLC (preparatoryscale, silica gel column, eluted with a mixture 19:1 methylene chloride:methanol eluant) to yield approxi- S: mately 7.0 g of the title product: n.m.r. (300 MHz, SCDC13) 6: 1.0 3H); 1.64 4H); 2.06 2H); 2.4 2H); 2.62 3H); 2.64 2H); 4.2 2H); 4.6 2H); 5.08 2H); 6.9 2H); 7.0 1H); 7.24 2H); 7.6 1H); 12.66 1H).
Analysis Calculated for C 25
H
30
N
4 0s: Theory: C, 64.36; H, 6.48; N, 12.01; Found: C, 64.59; H, 6.68; N, 11.80.
o 4 L -e x-38 -79 Example 36 1- [2-Hydroxy-3-propyl-4- i-tetrazol-5-yl)propyl]-2H-tetrazol-5-ylphenoxymethylphenyl..
ethanone ((4-Acetyl-3-hydroxy-2-propylphenyl methoxy)phenyl]-2B-tetrazole-2-(4-butyronitrile) (4.5 g, 0.11 mol) and tri(n-butyl)tin azide (33.2 g, 0.10 mol) were combined in DME. The resultant reaction solution was heated and stirred at reflux temperature for 3 days then poured into a 50/50 mixture of toluene/l0% aqueous hydrochloric acid. The resultant precipitate was collected by filtration and recrystallized from a mixture of ethanol and water to yield 4 g, 80% of the title product: m.p. 194-196 0
C.
(300 M~z, DMSO-d 6 6: 0.9 3H); 1.6 (in, 2H); 2.4-2.6 (in, 4H); 2.7 (t s, 5B); 3.0 2H); 4.95 2H); 5.25 2B); 7.1 l1H); 7.2 2H); 7.8 l1H); 8.0 2H); 12.7 1H).
Analysis Calculated for C 2 2
H
2 9
N
8 0 3 Theory: C, 59.73; H, 5.67; N, 24.23; Found: C, 60.01; B, 5.87; N, 24.03.
~I I r- I X-7387 Example 37 1-[4-[[4-[2-[3-(Dimethylamino)propyl]-2Htetrazol-5-yl]phenoxy]methyl]-2-hydroxy-3-propylphenyl]ethanone 5-[4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl]-2-(3-bromopropyl)-2H-tetrazole (2.8 g, 0.006 mol) was dissolved in acetonitrile and cooled to approximately 0°C. Dimethylamine (anhydrous, excess) was cooled in the reagent bottle before it was opened then added to the cool acetonitrile solution. The solution was maintained at approximately 0 C with an ice bath while it was stirred (approximately 5 hours). The reaction mixture was then concentrated in vacuo. Water was added and the resultant solution was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with water and dried over sodium sulfate. The dried ethyl acetate layers were concentrated and the resultant residue was chromatographed by HPLC (preparatoryscale, silica gel column, eluted isocratically with a mixture of 9.5 0.5 methylene chloride:methanol to which 0.05% of diethylamine had been added to yield 2.3 g, 88.5% yield of the title product: m.p. 89-91 0
C;
(300 MHz, CDC1 3 6: 1.0 2H); 1.6 2H); 2.1 2H); 2.2 6H); 2.3, 2H); 2.4 2H); 2.6 3H); 2.7 2H); 4.7 2H); 5.2 2H); 7.1 (2d, 3H); 7.6 1H); 8.1 2H); 12.7 1H).
Analysis Calculated for C 24 H3iNsOs: Theory: C, 65.88; H, 7.14; N, 16.01; Found: C, 66.11; H, 7.08; N, 16.23.
r
'I
X- 7387 -81- Example 38 1- [2-Hydroxy-3-propyl-4- (lHtetrazol-5-yl)phenyl]methyl]-2H-tetrazol-5-ylimethyl]phenoxy]methyl]phenyl] ethanone A mixture of 4.81 g (0.01 mol) of acetyl-3-hydroxy-2-propylphelyl )methoxy )phenyl )methyl] 2H-tetrazol-2-(ct-(p-tolunitrile)) and 12.18 g (0.037 mol) of tri(n-butyl)tin azide in 100 mL of 1,2-dimethoxyethane was heated to maintain reflux for 48 hrs, cooled, poured into 1 liter of 5% HCl, 200 mL toluene, and 300 mL of hexane, stirred 1 hr, and the precipitate filtered.
Two recrystallizations from 90% EtOH gave 2.3 g of the title compound: m.p. 86-88WC; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 3H); 1.52 (in, 2H); 2.62 (in, 5H); 4.2 2H); 5.12 2H); 6.0 2H); 6.93 2H); 7.06 1H1); 7.2 2H); 7.56 2H); 7.8 1H); 8.06 2H); 12.7 1H); Analysis Calculated for C 28
H
28
N
8 0 3 Theory: C, 64.11; H, 5.38; N, 21.36; Found: C, 62.79; H, 4.98; N, 20.50.
X-7387 -82- Example 39 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-methylsulfinylpropyl)-2Htetrazole 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-methylthiopropyl)-2Htetrazole (2.3 g, 0.005 mol) was dissolved in methanol (75 ml). Sodium periodate (1.1 g, 0.00525 moles) was dissolved in water (25 ml) and the aqueous solution was added to the methanol solution. The reaction mixture was stirred overnight at room temperature then diluted with water (100 ml). The diluted reaction mixture was extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated.
The concentrate was chromatographed by preparatory-scale HPTC (silica column) eluted isocratically with a mixture of 8:2 toluene:ethyl acetate to yield an oil of the title product: n.m.r. (300 MHz, CDC13) 6: 1.0 3H); 1.6 2H); 2.5 2H); 2.55 3H); 2.6 3H); 2.6-2.8 4H); 4.2 2H); 5.7-5.8 2H); 5.1 (s, 2H); 6.8 2H); 7.0 2H); 7.2-7.3 2H); 7.6 (d, 2H); 12.7 1H).
Analysis Calculated for C 24
H
30
N
4 0 4
S:
Theory: C, 61.26; H, 6.63; N, 9.97; SFound: C, 61.05; H, 6.68; N, 10.08.
-I X-7387 -83- Example 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-methylsulfonylpropyl)-2Htetrazole 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)methoxy)phenyl)methyl]-2-(3-methylthiopropyl)-2Htetrazole (2.0 g, 0.0044 mol) was dissolved in methylene chloride. Meta-chloroperbenzoic acid (1.6 g) was added slowly to the methylene chloride solution. The reaction mixture was stirred for one hour at room temperature then diluted with methylene chloride. The mixture was washed with saturated aqueous sodium bicarbonate solution and water. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The concentrate was precipitated from ethanol/water to yield the title product: m.p. 89-91 0 C; n.m.r. (300 MHz, DMSO-d 6 6: 0.9 3H); 1.4-1.6 2H); 2.3-2.4 2H); 2.5 (t, 1H); 2.6-2.7 (overlapping peaks, 5H); 3.2 2H); 3.3 3H); 4.2 2H); 4.8 2H); 5.15 2H); 6.9 (d, 2H); 7.1 1H); 7.2 2H); 7.8 1H); 12.7 1H).
Analysis calculated for C 24
H
30
N
4 0 5
S:
Theory: C, 59.24; H, 6.21; N, 11.51; Found: C, 59.38; H, 6.34; N, 11.47.
c i I SX-7387 -84- Example 41 Hard gelatin capsules are prepared using the following ingredients: Quantity (mg/capsule) 1-[2-Hydroxy-3-propyl-4 [3-(lH-tetrazol-5-yl)propyl]-2Hmethyl]phenyl]ethanone 250 Starch 200 Magnesium stearate The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
SExample 42 A tablet is prepared using the ingredients below: Quantity (mg/tablet) 1-[2-Hydroxy-3-propyl-4[[4-[[2- [3-(lH-tetrazol-5-yl)propyl]-2Hmethyl]phenyl]ethanone 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed Magnesium stearate V 11 1 ~rm~ ii r rr- X-7387 The components are blended and compressed to form tablets each weighing 665 mg.
Example 43 An aerosol solution is prepared containing the following components: Weight 10 1-[2-Hydroxy-3-propyl-4[[4-[[2- [3-(lH-tetrazol-5-yl)propyl]-2Hmethyl]phenyl]ethanone 0.25 Ethanol 30.00 Propellant 11 10.25 (trichlorofluoromethane) Propellant 12 29.75 (Dichlorodifluoromethane) Propellant 114 29.75 (Dichlorotetrafluoroethane) The active compound is dissolved in the ethanol and the solution is added to the propellant 11, cooled to -30 0 C and transferred to a filling device.
The required amount is then fed to a container and further filled with the pre-mixed propellants 12 and 114 by means of the cold-filled method or pressurefilled method. The valve units are then fitted to the container.
I
X-7387 *P6- Example 44 Tablets each containing 60 mg of active ingredient are made up as follows: 1-[2-Hydroxy-3-propyl-4-[[4-[[2-[4-(lHmethyl]phenoxy]methyl]phenyl]ethanone Starch Microcrystalline cellulose Polyvinylpyrrolidone (as 10% solution in water) Sodium carboxymethyl starch Magnesium stearate Talc Total 60 mg 45 mg 35 mg 4 mg 4.5 mg 0.5 mg 1 mg 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50-60 0 C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
r_ i- C~~i I X-7387 -87- Example Capsules each containing 80 mg of medicament are made as follows: 1-[2-Hydroxy-3-propyl-4[[4-[[2- [3-(lH-tetrazol-5-yl)propyl]-2Hmethyl]phenyl]ethanone 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, cellulose, starch and magnesium stearate are blended, passed through a No. mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities.
Example 46 Suppositories each containing 225 mg of active ingredient are made as follows: 25 1-[4-[[4-[[2-[3,3-Dimethyl-4-(1Htetrazol-5-yl)butyl]-2H-tetrazol- 5-yl]methyl]phenoxy]mathyl]-2hydroxy-3-propylphenyl]ethanone 225 mg Unsaturated or saturated fatty i acid glycerides to 2,000 mg PIm-
I
X-7387 -88- The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool.
Example 47 Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows: 1-[2-Hydroxy-3-propyl-4[[4-[[2- [3-(lH-tetrazol-5-yl)propyl]-2Hmethyl]phenyl]ethanone Sodium carboxymethyl cellulose Sugar Methyl paraben Propyl paraben Flavor Color Purified water to 50 mg 50 mg 1 g 0.05 mg 0.03 mg q.v.
q.v.
5 ml The medicament is passed through a No. mesh U.S. sieve and mixed with the sodium carboxymethylcellulose, sugar, and a portion of the water to form a suspension. The parabens, flavor and color are dissolved and diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
Claims (12)
1. A compound of the Formula I R a R R R4 d d Ri e-(CH2) n--Tet] I R R wherein: R I is C z to C 3 alkyl; R2 is Ci to C 6 alkyl or C 3 to C 6 alkenyl; R 3 is a hydrogen atom, chloro, bromo nitro, or a group of the formula -NR R ab wherein R and Rb are the same or different and are a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl, or Ci to C 4 acyl; R 4 and Rs are the same or different and are a hydrogen atom or C, to C 3 alkyl; W is from one to six; Z is 0, S or a group of the formula -NR (wherein R e is a hydrogen atom, CI to C 4 alkyl, C 1 to C 4 acyl, phenyl, or benzyl); n is 0 to 6; A. R and Rd are the same or different and are hydrogen, hydroxy, halo or an ether group of the formula -O-(Ci to C 6 alkyl); X-7387-(C) [Tet] is a disubstituted 1H- or 2H-tetrazoly. ring of the formula N A-L-4====Nor A wherein: L is 1) C 1 to C 10 alkylidene; or 2) a group of the formula os 25 0 wherein y is 1 to 3 (and the phenyl ring is bonded to A); A is 1) 2) carboxy; X-7387-(C) -91- 3) -NRfRg, wherein Rf and R are the same or different and are a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl or CI to C 4 acyl; or 4) a group of the formula (0) -(S)-Rh wherein q is 0, 1 or 2 and Rh is C 1 to C 4 alkyl, phenyl or benzyl; or a pharmaceutically-acceptable salt thereof.
2. A compound of claim 1, wherein: RI is methyl; R 2 is n-propyl; R 3 R 4 Rs, R c Rd are a hydrogen atom; Z is 0; W is 1; n is 0 or 1; [Tet] is a group of the formula: or L-A L is 1) CI to C 6 alkylidene; or X-7387-(C) -92- 2) a group of the formula -(CH 2 )y y wherein y is one (and the phenyl ring is also bonded to A); A is 1) 2) a group of the formula -NR R f g wherein Rf and R are each f g methyl; 3) a group of the formula (0) i q h wherein R h is methyl; or 4) a carboxylic acid; or a pharmaceutically-acceptable salt thereof.
3. 1-[2-Hydroxy-3-propyl-4[[4-[[2-[3-(lH-tetra- zol-5-yl)propyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]- phenyl]ethanone or a pharmaceutically-acceptable salt thereof. ii X-7387-(C) -93-
4. A compound of the Formula II Ra R Rd w-Z -o n-Tet-L-B] R1 R O \R2 II wherein: R 1 is Ci to C 3 alkyl; R 2 is CI to C 6 alkyl or C 3 to C 6 alkenyl; R 3 is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NR R b ab wherein R and Rb are the same or dif- ferent and are a hydrogen atom, CI to C 4 alkyl, phenyl, benzyl, or Ci to C 4 acyl; R 4 and Rs are the same or different and are a hydrogen atom or C, to C 3 alkyl; W is from one to six; Z is 0, S or a group of the formula -NR e (wherein Re is a hydrogen atom, CI to C 4 alkyl, phenyl, benzyl or Ci to C 4 acyl); n is 0 to 6; R and R are the same or different and are a c d hydrogen atom; hydroxy, halo or an ether group of the formula -0-(Ci-C 6 alkyl); -A I_ __I~_LI_1I/ a X-7387-(C) -94- [Tet-L-B] is a disubstituted 1H- or 2H- tetrazolyl ring of the formula I N or -3 L--B wherein: L is 1) 2) C 1 to CIo alkylidene; or a group of the formula oo 25 a C (3 i 3 '3 -(CH y wherein y is 1 to 3 (and the phenyl ring is also bonded to and X-7387-(C) B is 1) cyano; 2) halo; or 3) a group of the formula -COOR e wherein Re is ethyl or a carboxy-protecting group. A compound of claim 4, wherein: R 1 is methyl; R 2 is n-propyl; R 3 R 4 Rs, R c Rd are each hydrogen; Z is 0; W is 1; n is 0 or 1; [Tet-L-B] is a disubstituted 1H- or 2H- tetrazolyl ring of the formula: or 2 L-B L is 1) Ci to C 6 alkylidene; or 2) a group of the formula -(CH2) Snwherein y is one (and the phenyl ring is also bonded to and B is cyano, bromo, or ethyl ester. -1 1 _I X-7387-(C) -96-
6. 5-[(4-((4-Acetyl-3-hydroxy-2-propylphenyl)- methoxy)phenyl)methyl]-2H-tetrazole-2-(4-butyronitrile).
7. A pharmaceutical formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, in association with one or more pharmaceutically accept- able carriers or diluents therefor. A compound of Formula ceutically-acceptable salt thereof-s claimed in any one of claims 1 to 3, for- e in treating a mammal suffering from or susceptible to any condition charac- -terized-by an excessive release of leukotr-i-ene----
8. A process for preparing a compound of Formula I as claimed in claim 1 which comprises: a) reacting a halo intermediate of Formula II R Rd R3 4 R 4 a R d R2-0 (CH)n--fTet-L-B] s \z II wherein: R I is CI to C 3 alkyl; R 2 is CI to C 6 alkyl or C 3 to C 6 alkenyl; 4 4 r, X-7387-(C) -97- R 3 is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NRaRb wherein Ra and Rb are the same o: dif- ferent and are a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl, or C 1 to C 4 acyl; R 4 and Rs are the same or different and are a hydrogen atom or C 1 to C 3 alkyl; W is from one to six; Z is O, S or a group of the formula -NR ('.iherein Re is a hydrogen atom, C 1 to C 4 alkyl, phenyl, benzyl or C, to C 4 acyl); n is 0 to 6; R and Rd are the same or different and are a c d hydrogen atom, hydroxy, halo or an ether group of the formula -0-(Ci-C 6 alkyl); [Tet-L-B] is a disubstituted 1H- or 2H- tetrazolyl ring of the formula 11\ X-7387-(C) -98- =B-L B-L or V-B wherein: L is 1) Ci to Clo alkylidene; or 2) a group of the formula Y wherein y is 1 to 3 and the phenyl ring is also bonded to B; and B is halo; with HNRfRg or HSRh, or b) hydrolyzing an intermediate of Formula II as defined above wherein B is cyano or -COOR 6 or c) reacting a nitrile intermediate of Formula II as defined above wherein B is cyano with an azide derivative, or d) oxidizing a compound of Formula I as defined in claim 1 wherein A is -SRh with an oxidizing agent, and e) optionally converting the resulting product into a pharmaceutically acceptable salt. A- c ompound-o f-the--Eormu-la-I- w-henever-- prcpared byaprce&s&s according to-G-oj g I 99
9. A compound of Formula as claimed in claim 1 and substantially as hereinbefore described with reference to any one of Examples 1 to A process for preparing a compound of Formula as defined in claim 1 and substantially as hereinbefore described with reference to any one of Examples 1 to
11. A compound of Formula whenever prepared by a process according to claim 8 or
12. A process of preparing a pharmaceutical formulation as claimed in claim 7, comprising mixing a compound of Formula as claimed in any one of claims 1 to 3 or 10 with a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
13. A pharmaceutical formulation comprising a compound as claimed in any one of claims 1 to 3 or 10 and substantially as hereinbefore described with reference to any one of Examples 40 to 47.
14. A process of preparing a pharmaceutical formulation as claimed in claim 13 and substantially as hereinbefore described with reference to any one of Examples 40 to 47. A method of treating a mammal which is suffering from or susceptible to any condition characterized by an excessive release of leukotrienes, said method comprising administering to said mammal an effective amount of a compound of Formula as defined in any one of claims 1 to 3, 9 or 11 or a pharmaceutically acceptable salt thereof and/or a pharmaceutical formulation as claimed in claim 7 or claim 13. DATED this FIRST day of MARCH 1991 Eli Lilly and Company Patent Attorneys for the Applicant SPRUSON FERGUSON TMS/1565R TMS/1565R
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US085586 | 1987-08-14 | ||
| US07/085,586 US4820722A (en) | 1987-08-14 | 1987-08-14 | Disubstituted tetrazoles and their use as leukotriene antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2096688A AU2096688A (en) | 1989-02-16 |
| AU610629B2 true AU610629B2 (en) | 1991-05-23 |
Family
ID=22192620
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU20966/88A Expired - Fee Related AU610629B2 (en) | 1987-08-14 | 1988-08-11 | Improvements in or relating to leukotriene antagonists |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4820722A (en) |
| EP (1) | EP0305085B1 (en) |
| JP (1) | JPS6466175A (en) |
| KR (1) | KR890003715A (en) |
| CN (1) | CN1013769B (en) |
| AT (1) | ATE92052T1 (en) |
| AU (1) | AU610629B2 (en) |
| DE (1) | DE3882619T2 (en) |
| DK (1) | DK449488A (en) |
| HU (1) | HUT50463A (en) |
| NZ (1) | NZ225793A (en) |
| PT (1) | PT88245B (en) |
| ZA (1) | ZA885888B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4853398A (en) * | 1987-04-13 | 1989-08-01 | Eli Lilly And Company | Leukotriene antagonists and use thereas |
| IL98405A0 (en) * | 1990-06-11 | 1992-07-15 | Fmc Corp | Pharmaceutical compositions containing enzyme inhibiting agents |
| US5210208A (en) * | 1990-09-24 | 1993-05-11 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Disubstituted aryl compounds exhibiting selective leukotriene b4 antagonist activity |
| DE4124942A1 (en) * | 1991-07-27 | 1993-01-28 | Thomae Gmbh Dr K | 5-LOW HETEROCYCLES, METHOD FOR THE PRODUCTION THEREOF AND MEDICAMENTS CONTAINING SUCH COMPOUNDS |
| RU2144533C1 (en) * | 1994-12-09 | 2000-01-20 | Такеда Кемикал Индастриз, Лтд. | Derivatives of tetrazole, method of their synthesis and pharmaceutical compositions based on them |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7455087A (en) * | 1986-06-23 | 1987-12-24 | Merck Frosst Canada Inc. | Leukotriene antagonists containing a 4-acetyl-3-hydroxy-2-propyl-phenyl moiety |
| AU1016488A (en) * | 1987-01-12 | 1988-07-14 | Eli Lilly And Company | Anti-inflammatory agents |
| AU2096788A (en) * | 1987-08-14 | 1989-02-16 | Eli Lilly And Company | Improvements in or relating to leukotriene antagonists |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4661505A (en) * | 1982-11-03 | 1987-04-28 | Eli Lilly And Company | Leukotriene antagonists |
| US5105017A (en) * | 1983-07-18 | 1992-04-14 | Eli Lilly And Company | Leukotriene antagonist intermediates |
-
1987
- 1987-08-14 US US07/085,586 patent/US4820722A/en not_active Expired - Fee Related
-
1988
- 1988-08-10 ZA ZA885888A patent/ZA885888B/en unknown
- 1988-08-10 JP JP63202628A patent/JPS6466175A/en active Pending
- 1988-08-11 NZ NZ225793A patent/NZ225793A/en unknown
- 1988-08-11 PT PT88245A patent/PT88245B/en not_active IP Right Cessation
- 1988-08-11 AU AU20966/88A patent/AU610629B2/en not_active Expired - Fee Related
- 1988-08-11 AT AT88307430T patent/ATE92052T1/en not_active IP Right Cessation
- 1988-08-11 DK DK449488A patent/DK449488A/en not_active Application Discontinuation
- 1988-08-11 DE DE88307430T patent/DE3882619T2/en not_active Expired - Fee Related
- 1988-08-11 EP EP88307430A patent/EP0305085B1/en not_active Expired - Lifetime
- 1988-08-12 KR KR1019880010273A patent/KR890003715A/en not_active Withdrawn
- 1988-08-12 HU HU884344A patent/HUT50463A/en unknown
- 1988-08-12 CN CN88106048A patent/CN1013769B/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7455087A (en) * | 1986-06-23 | 1987-12-24 | Merck Frosst Canada Inc. | Leukotriene antagonists containing a 4-acetyl-3-hydroxy-2-propyl-phenyl moiety |
| AU1016488A (en) * | 1987-01-12 | 1988-07-14 | Eli Lilly And Company | Anti-inflammatory agents |
| AU2096788A (en) * | 1987-08-14 | 1989-02-16 | Eli Lilly And Company | Improvements in or relating to leukotriene antagonists |
Also Published As
| Publication number | Publication date |
|---|---|
| ATE92052T1 (en) | 1993-08-15 |
| EP0305085B1 (en) | 1993-07-28 |
| ZA885888B (en) | 1990-04-25 |
| DK449488D0 (en) | 1988-08-11 |
| CN1031223A (en) | 1989-02-22 |
| PT88245B (en) | 1995-03-01 |
| DE3882619D1 (en) | 1993-09-02 |
| KR890003715A (en) | 1989-04-17 |
| DE3882619T2 (en) | 1993-12-23 |
| AU2096688A (en) | 1989-02-16 |
| DK449488A (en) | 1989-03-17 |
| US4820722A (en) | 1989-04-11 |
| PT88245A (en) | 1989-06-30 |
| HUT50463A (en) | 1990-02-28 |
| CN1013769B (en) | 1991-09-04 |
| JPS6466175A (en) | 1989-03-13 |
| NZ225793A (en) | 1990-10-26 |
| EP0305085A1 (en) | 1989-03-01 |
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